Irritable Bowel Syndrome, Diarrhea, and Constipation (RHCHP School of Pharmacy) PDF

Irritable Bowel Syndrome, Diarrhea, and Constipation RHCHP School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Readings and References Kathryn Miller, Ph...

Irritable Bowel Syndrome, Diarrhea, and Constipation RHCHP School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Readings and References Kathryn Miller, PharmD Required [email protected] Integrated Pharmacotherapy 2 Irritable Bowel Syndrome, Diarrhea, and Constipation notes Peter Cogan, PhD Optional [email protected] Review of Medical Physiology, Chapter 25 and Chapter 26 (AccessPharmacy) 303-964-6154 Basic & Clinical Pharmacology, Chapter 63: Opioid section of “Antidiarrheal Agents” and 5-HT3 Antagonist section of “Drugs Used in the Treatment of IBS” (AccessPharmacy) Netter’s Illustrated Pharmacology pages 181-182 and 185 Learning Objectives 1. Differentiate between diarrhea, constipation and irritable bowel syndrome. 2. Compare and contrast the anatomy and structure of the small and large intestine. 3. Compare and contrast the digestive process for carbohydrates, proteins, and lipids. 4. Explain fluid and electrolyte absorption in the intestines. 5. Define the role of the following intestinal cells: enterocytes, goblet cells, and stem cells in the crypts of Lieberkuhn. 6. Describe intestinal secretion and the role of chloride and potassium in this process. 7. Describe the function of intestinal motility. 8. Differentiate between the types of intestinal motility. 9. *Explain the function of the enteric nervous system and how it interacts with the autonomic nervous system to control digestion. 10. Differentiate between the following types of diarrhea: secretory, osmotic, exudative, and altered motility/dysmotility. 11. Recognize the clinical presentation of IBS, including signs and symptoms, non-GI symptoms, concurrent conditions, and effect on health-related quality of life. 12. Identify the Rome IV diagnostic criteria for IBS. 13. Recognize alarm symptoms which indicate the need for further gastroenterology evaluation. 14. Describe the goals of therapy for diarrhea, constipation, and IBS. 15. Describe nonpharmacologic approaches used in the management of IBS. 16. Predict the effect of activation or antagonism of opioid receptors, 5-HT3 and 5-HT4 receptors, and chloride channels on the gastrointestinal tract. 17. Identify the pharmacologic classification and describe the mechanism of action for the medications in this note packet that are used for the management of IBS, diarrhea, or constipation. 18. Explain the rationale for combining atropine with diphenoxylate. 19. Recognize anticholinergic side effects and the medications and classes that cause these effects. 20. *Correlate the tissue distribution of diphenoxylate and loperamide with the abuse potential of each medication. 21. *Understand the role that P-glycoprotein plays in determining the distribution of loperamide. 22. For the drugs used in the management of IBS, diarrhea, or constipation, describe the various routes of administration available for drug dosing, and explain the advantages and disadvantages of each. 23. List the medications and drug classes used to manage IBS. 24. Identify common and serious adverse effects of medications used in management of IBS. 25. Identify mechanisms by which drug-drug interactions occur with diphenoxylate/atropine and alosetron. 26. Identify any special considerations and safety concerns, including black-box warnings, associated with the drugs in this note packet. 27. Recognize factors implicated in the exacerbation of IBS symptoms and recommend appropriate corrective measures. 28. Explain the risks and benefits of medications used to treat constipation-predominant IBS (IBS-C) and diarrhea-predominant IBS (IBS-D). 29. Describe adverse effects of medications used in the management of IBS-C and IBS-D. 30. Describe the role and place in therapy of medications used in the treatment of IBS, including recommendations by the American College of Gastroenterology (ACG). 31. Demonstrate the ability to counsel a patient on nonpharmacotherapy, complementary and alternative medicine, and pharmacotherapy for IBS. 32. *Given a patient case, develop an evidence-based treatment plan for a patient with IBS-D or IBS-C. *Learning objectives marked with an asterisk will not be assessed on the RAT but may be assessed in application exercises and exams. INTRODUCTION The disease states covered in this packet are very common and disrupt the lives of millions of people every year. You will learn about diarrhea and constipation primarily in the Therapeutic Principles of Self-Care course, as management is predominantly with over- the-counter medications. In addition, opioid-induced constipation, as well as travelers’ diarrhea, will be covered in future Integrated Pharmacotherapy courses. The focus of this unit will be irritable bowel syndrome, which is often characterized predominantly by diarrhea (IBS-D) or constipation (IBS-C). Note that diarrhea can occur independently of a diagnosis of IBS-D, and constipation alone can also occur in the absence of IBS-C. Specific diagnostic criteria for IBS is discussed in the Clinical Presentation section of these notes. Diarrhea Diarrhea is a common problem that affects most people at one point in their lives. Diarrhea is typically defined as increased frequency and decreased consistency of stools compared to an individual’s normal stools. There is a large variety of “normal stools” across cultures and diets, it is important to know what the individual’s stools are typically like. In most cases, diarrhea resolves on its own in a few days, but sometimes it can last much longer. Diarrhea that lasts less than 14 days is typically considered acute diarrhea, whereas diarrhea lasting 14 to 30 days is called persistent diarrhea. If the symptoms last longer than 30 days, it is known as chronic diarrhea. It is often a symptom of a more serious disease, but can occur by itself as well. Diarrhea may be caused by problems within the intestines, or be secondary to a non-GI disease. Constipation Also very common, constipation is often self-treated with over the counter medications. The American College of Gastroenterology Task Forces defines constipation as “a symptom-based disorder defined as unsatisfactory defecation and is characterized by infrequent stools, difficult stool passage, or both.” Difficult stool passage includes straining, a sense of difficulty passing stool, incomplete evacuation, hard/ lumpy stools, prolonged time to stool, or the need for manual maneuvers to pass stool. Chronic idiopathic constipation (CIC) is defined as the presence of these symptoms for at least 3 months. One of the major causes of constipation in the United States is the lack of sufficient fiber in the diet. Another underlying problem is the misconception that stool frequency should be the same for everyone. As mentioned above, there is a wide variety in the normal frequency of bowel movements, with some people defecating several times per day and some only a few times per week. This confusion about normal frequency can cause constipation to be underdiagnosed and overtreated. Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a disorder defined by the American College of Gastroenterology Task Forces as “abdominal discomfort associated with altered bowel habits.” IBS is characterized by recurrent symptoms of abdominal pain, altered bowel function, and varying complaints of flatulence, bloating, nausea, anorexia, constipation, diarrhea, anxiety, and/or depression. IBS is caused by a combination of several factors such as poor regulation of the muscle contractions of the GI tract which causes dysmotility, visceral hypersensitivity of the nerves of the intestinal tract and brain-gut dysfunction in miscommunication between the central nervous system and the enteric nervous system. These will be discussed in detail later in the packet. To be diagnosed as IBS, the disorder needs to be without a known cause (idiopathic). IBS affects 7 to 10% worldwide and roughly 10 to 15% of adults in the United States. Although most do not seek medical attention, IBS results in impaired health-related quality of life, medical expenses, and decreased work productivity. IBS tends to affect women almost twice as much as men, and is typically diagnosed before 50 years of age. Menarche often is associated with onset of the disorder and women frequently notice a worsening of symptoms during the premenstrual period. People with IBS tend to experience symptoms during times of psychological and physiologic stress. The role of psychological factors in the disease is still unknown. Although changes in intestinal activity are normal responses to stress, these responses appear to be exaggerated in those with IBS. GASTROINTESTINAL PHYSIOLOGY Small Intestine The small intestine is made up of three sections, the duodenum, the jejunum, and ileum. Chyme (food and digestive enzymes) passes from the stomach through the pyloric sphincter and enters the duodenum in small spurts containing tiny suspended particles. The small intestine is the primary site for the mixing of chyme with additional secretions from the common bile duct and pancreatic duct promoting digestion and absorption. Integrated Pharmacotherapy 2 2 Irritable Bowel Syndrome, Diarrhea, and Constipation Figure 1. Anatomy of the small and large intestine Goblet cells are scattered throughout the villi and crypts. They secrete mucus into the intestinal lumen. Mucus protects the surface area of the mucosa, lubricates the intestinal contents, and holds antibodies in place. The microvilli are plasma membrane evaginations that contain many of the enzymes involved in the digestive process. The microvilli form a layer called the brush border. The surface epithelial cells of the villi consist mostly of enterocytes which are absorptive cells. These epithelial cells contain microvilli. A villus is approximately 1mm in height and there are 20 to 40 Located at the base of the villi are crypts of Lieberkuhn which villi per square millimeter of mucosa. Each villus is covered by contain a variety of cell types that produce and secrete buffers, a single layer of epithelial cells and contains a network of enzymes, and hormones that facilitate digestion and absorption. The capillaries and lymphatic vessels extending from the smooth crypts also contain stem cells that differentiate into one of the muscle of the sub mucosa running longitudinally to the villi’s various cell types covering the villi. tip. Image Source http://histologyolm.stevegallik.org/node/411 Functional Anatomy The small intestine (Figure 1) provides a substantial surface area over which digestion and absorption occurs. The following factors contribute to the large surface area of the small intestine: The length of the small intestine (approximately 5 meters) The many folds of the mucosa and sub mucosal layers of the intestine wall On the mucosal layer of the intestine wall there are finger-like projections called ‘villi’ which extend into the lumen (hollow interior space of the GI tract) dramatically increasing absorptive surface area On each epithelial cell there are ‘microvilli’ on the apical surface which also help increase surface area It is estimated that the mucosal and sub mucosal folds, villi and microvilli combined increase the absorptive surface area of the small intestine by about 600 fold. To allow for rapid and efficient movement of nutrients into the blood, there is only one layer of epithelial cells between the intestinal lumen and systemic blood. It is interesting to note that the cells that are located at the base of the villi differentiate as they migrate toward the tip of the villi and are eventually shed into the intestinal lumen after about 2 to 6 days. In humans, approximately 17 billion cells are shed per day. Digestion & Absorption in the Small Intestine The primary physiological function of the small intestine is the digestion and absorption of ingested nutrients (carbohydrates, proteins, and lipids). Here we discuss the steps of digestion and the mechanisms by which nutrients are absorbed. Carbohydrates Dietary carbohydrates are mostly composed of polysaccharides (starch) and disaccharides (sucrose and lactose). Because enterocytes can only absorb monosaccharides, carbohydrates must be digested to monosaccharides or simple sugars (glucose, galactose, and fructose). Carbohydrate digestion occurs in two stages: in the intestinal lumen and on the surface of the brush border. Digestion of starches is initiated in the oral cavity by salivary amylase and continues in the duodenum by pancreatic amylase. Amylase cleaves the internal bonds of polysaccharides to form fragments (di-, tri-, and oligosaccharides). Enzymes (hydrolases) at the brush border then digest the disaccharides and oligosaccharides into monosaccharides. Because the monosaccharides are water-soluble, they must be assisted across the plasma membrane of the enterocyte by the action of transport proteins (Figure 2). Integrated Pharmacotherapy 2 3 Irritable Bowel Syndrome, Diarrhea, and Constipation Figure 2. Mechanism for glucose transport across intestinal epithelium. Na /K ATPase, located on the 1 The + + basolateral membrane, provides the necessary Na+ concentration gradient which drives the absorption of glucose and galactose. It pumps Na+ out of the cell so the 2 Na+ is transported down its concentration gradient and drives the intracellular concentration of Na+ is low, absorption of glucose and galactose allowing the SGLT-1 transporter on the luminal which are absorbed against their membrane to work. concentration gradient. The sodium/glucose transporter 1 3 (SGLT-1) co-transports either glucose or galactose with two Na+ ions across the apical membrane into the cell. The monosaccharides (glucose/galactose) are 4 either used for cell metabolism or transported by facilitated diffusion out of the cell by glucose transporter 2 (GLUT-2). In other words, the high concentration of monosaccharides that build up inside the cell GLUT-5 (not pictured) allows for fructose allows for monosaccharides to move out of the 5 to diffuse into the cell when concentrations cell down their concentration gradient with no of fructose are high in the intestinal lumen. energy expenditure. This transporter requires no energy expenditure or co-transport with another ion. Lipids Lipid digestion and absorption are summarized in Figure 3. Because lipids are almost entirely insoluble in water, lipids tend to aggregate together. Therefore, the first step in dietary lipid digestion is emulsification, a mechanical process producing a suspension of fine lipid droplets. Bile salts, released by the liver, aid in the emulsification of lipids. Next, lipids are chemically digested by the use of lipases, taking place primarily at the brush border of the intestine. Other lipases include phospholipase which hydrolyzes phospholipids and cholesterol esterase which primarily breaks down esters in cholesterol. Proteins Proteins must also be digested to tri- and dipeptides, and individual amino acids for transport into enterocytes. Digestion of proteins begins in the stomach where the acidic environment can hydrolyze peptide bonds. The chief cells of the stomach release pepsinogen, which is activated by the low pH to an active form called pepsin. Pepsin, which functions best in an acidic environment, preferentially hydrolyzes the peptide bond following aromatic amino acids such as phenylalanine, tryptophan, and tyrosine. Because these amino acids Figure 3. Lipid digestion and absorption. The  primary  form  of  lipid  ingested  by  humans   The  majority  of  lipolysis  (lipid  diges4on)  occurs  in   is  the  triglyceride.  Structurally,  triglycerides   the  small  intes4ne  where  pancrea4c  lipase  also   have  long-­‐chain  fa=y  acids  connected  to  a   plays  an  important  role  in  the  diges4on  of  lipids.   glycerol  backbone.  Other  lipids  that  are  also   Pancrea4c  lipase  breaks  down  lipids  through   consumed  include  cholesterol,  phospholipids,   hydrolysis  resul4ng  in  monoacyl-­‐glycerol  and   fa=y  acids,  and  fat-­‐soluble  vitamins.     smaller  fa=y  acids  which  then  can  be  absorbed   through  the  intes4nal  lining.   The  first  step  in  the  diges4on  of  dietary  lipid  is   emulsifica0on.  Emulsifica4on  is  a  mechanical   process  that  occurs  through  chewing  in  the   mouth  and  contrac4ons  in  the  stomach  which   results  in  a  suspension  of  fine  lipid  droplets.   Small  fa=y  acids  (less  than  10  to  12   Lipases  released  in  the  saliva  and  by  chief  cells   carbon  atoms)  can  readily  diffuse  into   begin  the  chemical  diges4on  of  lipids.  Bile  salts   the  enterocyte  whereas  longer-­‐chain   adsorb  to  the  lipids  to  form  micelles  (aggregates   fa=y  acids  are  likely  absorbed  by   of  bile  salts  and  small  lipids).  The  detergent   specific  microvillus  membrane  fa=y   ac4on  of  bile  emulsifies  the  micelles  into  smaller   acid-­‐binding  protein.     fat  droplets  further  increasing  their  surface   area.  The  forma4on  of  micelles  also  allows  lipids   to  move  closer  to  the  brush  border  of  the   intes4ne.   Once  inside  the  enterocyte,  the   products  of  lipolysis  are   recombined  into  triglycerides,   phospholipids,  and  cholesterol   Chylomicrons  are  exported  from  the   esters  and  packaged  with   basolateral  membrane  and  enter  the   specific  transport  proteins   circula4on  via  the  lympha4c  system.     (apolipopro0ens)  to  form   chylomicrons.   Integrated Pharmacotherapy 2 4 Irritable Bowel Syndrome, Diarrhea, and Constipation only constitute a few of the total amino acids, more complete digestion of proteins requires additional proteases released by the pancreas. In a similar fashion to the stomach, the pancreatic proteases are released as inactive precursors which are converted to active enzymes. Specifically, trypsinogen is converted to trypsin which, in turn, activates all other pancreatic proteases. Final digestion of the resultant oligopeptides occurs by the brush border proteases producing tripeptides, dipeptides, or individual amino acids. These molecules are transported into the cells via secondary active transport with sodium (amino acids), or coupled with H+ symporters (dipeptides and tripeptides). Amino acid transporters generally have broad specificity and each transporter is specific for various side chain groups: acidic, basic, neutral, or imino. The dipeptides and tripeptides are then digested by cytosolic peptidases to individual amino acids. Fluid and Electrolytes The small intestine is the major site for water and electrolyte absorption. Water absorption is passive and mostly occurs by a transcellular route via water channels (aquaporins). Even though epithelial cells are interconnected by tight junctions, small amounts of water can move in a paracellular route. In the duodenum and jejunum, tight junctions are leaky and become progressively tighter in the ileum and colon. It is important to point out that water can move in both directions across the mucosa depending on the osmotic gradient. Depending on the intestinal contents, the osmolarity of duodenal contents may be hypertonic or hypotonic to that of the plasma. However, by the time the contents enter the jejunum, its osmolarity is similar to plasma and is maintained throughout the rest of the small intestine. Sodium absorption is mainly transcellular, traveling through the cell, passing through both the apical and basolateral membranes. The Na+/K+ ATPase in the basolateral membrane (surface of the cell opposite the side of the intestinal lumen) maintains low intracellular concentrations of Na+ allowing for luminal Na+ to enter the enterocytes. As previously mentioned, sodium transport is primarily coupled with glucose and some amino acids. It is important to note that glucose can also drive sodium reabsorption. There is some Na+ and Cl- absorption through a paracellular route. Chloride ions are also reabsorbed through an antiport exchanger in which bicarbonate ions are secreted into the lumen. HCO3- acts to protect the epithelial cells in the most proximal sections of the duodenum where acid and pepsin are in high levels. The movement of electrolytes and nutrients from the intestinal lumen into the blood creates the osmotic gradient that drives water absorption. Secretion in the Small Intestine Figure 4. Intestinal secretion of sodium and chloride. Although the net movement of water and electrolytes in the small intestine is primarily absorptive, electrolyte secretion can occur. Some K+ is secreted through K+ channels into the intestinal lumen. Chloride ions are secreted into the intestinal lumen via chloride channels located in the apical membrane (Figure 4). The movement of negatively charged ions provides an electrical gradient in which Na+ ions are also secreted through a paracellular route. The result of increased ions in the intestinal lumen causes an increase in the osmotic concentration. Water will move from plasma into the lumen to maintain equal solute concentrations in both the plasma and intestinal lumen. As you will read later in the packet, this is the target of drug therapy for patients suffering from constipation. By increasing the amount of ions in the intestinal lumen, and the resulting water content, contents in the intestinal tract will be able to pass more freely. Fluid and electrolyte secretion acts to protect the mucosal layer by flushing bacterial products and toxins away from the epithelial cells. Numerous neural and paracrine signalling molecules stimulate fluid and electrolyte secretion in both health and disease. Motility of the Small Intestine Figure 5. Diagram of contractions of the intestine Intestinal smooth muscle in the muscularis layer mix chyme with pancreatic bile and intestinal secretions, and propel food through the small intestine by coordinated waves of contractions. Smooth muscle contracts in two different ways: segmentation contractions and peristaltic waves. In segmentation, nonadjacent segments of the intestines rhythmically contract and relax moving food in both directions mixing intestinal contents with cell secretions (Figure 5). This process slows transit increasing contact time between the chyme and epithelial cells allowing for absorption. Peristaltic waves propel chyme forward through the small intestine toward the large intestine. In this process, adjacent segments of intestine alternately contract and relax propelling food forward along the tract. Peristalsis occurs late in the digestion process only after most nutrients have been absorbed. The smooth muscle of the intestine contracts with (A) mixing segmentation, and well as with (B) peristaltic movements. Integrated Pharmacotherapy 2 5 Irritable Bowel Syndrome, Diarrhea, and Constipation Colon The large intestine frames the small intestines consisting of the ascending, transverse, and descending segments (Figure 6). The functions of the colon are to complete digestion, absorb most of the remaining water and electrolytes, secrete mucus, and store the unabsorbed material until it can be eliminated from the body. The wall of the large intestine differs from the small intestines in that there are few folds, no villi, virtually no cells that secrete digestive enzymes, and a large number of goblet cells which secrete mucus. Once the unabsorbed material reaches the large intestine, very few nutrients remain. Very little further digestion occurs except for the small amounts of digestion by the intestinal microbial flora. Similar to the small intestine, water absorption is coupled to electrolyte (particularly sodium and chloride) movement. Figure 6. Large intestine or colon The Enteric Nervous System Basic Anatomy of the ENS The digestive tract is equipped with its own nearly self-contained nervous system. The enteric nervous system (ENS) is comprised of a variety of nerve fiber types distributed throughout the entire alimentary tract, from the esophagus to the anus. There are approximately 100 million nerve fibers within the ENS, rivaling the number found in the entire spinal chord. The majority of these nerve fibers run along the alimentary tract and are found distributed within the walls of the gastrointestinal tissues. Other nerve fibers enter and leave the ENS to maintain communication with higher control centers found in the autonomic nervous system (ANS) and central nervous system (CNS). We will first survey the distribution and functions of the different types of nerves which make up the ENS and then discuss some of the specific signalling pathways which may be targeted in the pharmacotherapeutic treatment of common GI disorders (see “Drug Distribution, Action and Effects” on page 11). The ENS is primarily localized in two extensive plexuses (web-like collections of nerves) running along the inner tissue layers of the GI tract. Figure 7 shows the location of the two plexuses. The myenteric plexus, or Auerbach’s plexus, is located between the longitudinal and circular muscle Figure 7. Intestinal cross section layers of the GI tract and is primarily responsible for control of muscular contraction and the mechanical aspects of digestion demonstrated in Figure 5 on page 5. The submucosal plexus, or Meissner’s plexus, lies in the submucosa and is primarily responsible for control of digestive secretions, absorption, and local contraction of the submucosal muscle, which leads to infolding of the mucosa. While the two plexuses can function on their own to maintain reasonable control of the digestive tract, the ENS must be able to respond efficiently to control signals sent from the sympathetic or parasympathetic nervous systems (the two branches of the ANS). Why does the gut need to respond to the ANS? Think about the “fight or flight” reflex. During times of acute stress, blood flow is reserved for organs vital to an appropriate response. Sympathetic signals inhibit GI activity, causing digestion to be suspended to save energy. Blood and nutrients are then redirected to skeletal muscles and the brain. Conversely, in times of rest and digestion, the parasympathetic nervous system increases the activity of the gut to ensure that replenishing nutrients, minerals, and water are obtained. Along with these efferent nerve fibers (carry signals into the ENS from the ANS), the ENS is also influenced by afferent nerve fibers which originate in the wall of the gut and carry signals from the alimentary canal into the ENS plexuses. This allows for the GI tract to respond to activity in the lumen of the gut, triggering local peristalsis and secretions. Some of these afferent fibers also leave the GI tract altogether and relay signals from the gut to prevertebral sympathetic ganglia (collection of nerve junctions which reside near the spinal chord). These signals evoke a reflex whereby distant portions of the GI tract can be controlled by effects elsewhere. For example, signals can be sent from the stomach to initiate colon motility as room is needed for newly digested food. Still other afferent nerve fibers run into the vagus nerve and all the way back to the brain stem, allowing for higher level control of all aspects of digestion. Thus, several levels of control are possible in response to events in the GI tract. Integrated Pharmacotherapy 2 6 Irritable Bowel Syndrome, Diarrhea, and Constipation Neurotransmitters of the ENS ENS Neurotransmitters There are more than a dozen neurotransmitters responsible for maintaining control of gastrointestinal Acetylcholine activity (see box at right). Some of these chemicals are excitatory, while others are inhibitory. Some Norepinephrine affect secretions into the lumen of the gut, while others control muscular contractions and gut motility. Epinephrine The ENS is remarkably complex, requiring crosstalk between all of these signals to control digestion. Overactivity or underactivity of these various signalling pathways can lead to excessive or diminished ATP secretions, excessive or diminished absorption, excessive motility, or prolonged residence of food and Serotonin (5HT) chyme in various compartments of the GI tract. Abnormal ENS function can also manifest as pain and Cholecystokinin (CCK) other sensations. You do not need to memorize all of these neurotransmitters and hormones, but some Substance P of them will be implicated in the pathophysiology of IBS, diarrhea, and constipation. In addition to these Vasoactive Intestinal Peptide (VIP) neurotransmitters, various paracrine cells (G cells, enterochromaffin like cells) of the GI tract, which are Somatostatin under the control of enteric neurons, secrete still more signaling molecules, further complicating the control of GI activity. Leu-enkephalin Met-enkephalin Bombesin PATHOPHYSIOLOGY Irritable Bowel Syndrome IBS is a complex disease and the cause is unknown. The following aspects can contribute to IBS: diet, genetics, motility factors, inflammation, colonic infections, mechanical irritation to local nerves, stress, and other psychological factors. IBS is often qualified depending on the symptoms experienced or the cause of the condition. IBS-D is predominantly marked by the experience of diarrhea while IBS-C sufferers are more prone to experience constipation as a defining symptom of the disorder. Of interest is the observation that peristaltic contractions occur less frequently in IBS-C patients than in those suffering from simple constipation, suggesting that the condition is not simply the result of secretory dysfunction of the GI tract. Be aware that “diarrhea” and “constipation” are only used as symptomatic descriptors of the syndrome and that the two conditions are not mutually exclusive; patients may alternate between an IBS-D and IBS-C predominant state. All are accompanied by chronic visceral (deep tissue) pain or discomfort in association with aberrant GI activity. Diarrhea Diarrhea can lead to dehydration, malnutrition, weight loss, specific vitamin deficiency, and potentially reduced drug absorption (especially extended release drugs). Diarrhea is classified by four general pathophysiologic mechanisms: secretory, osmotic, exudative, and altered motility/dysmotility. Secretory Diarrhea Secretory diarrhea results when a substance causes elevated rates of fluid transport into the intestinal lumen through increased secretion or decreased absorption of water and electrolytes. Stimulative substances include hormones, unabsorbed dietary fat, laxatives, bacterial toxins, and excessive bile salts. Secretory diarrhea produces large stool volumes (>1 liter per day) with normal ionic contents and osmolality equal to plasma. Stool volume does not change with fasting. Broad clinical diarrheal groups Osmotic Diarrhea Secretory Osmotic diarrhea results from the ingestion of poorly absorbed nutrients that retain Increases secretion or decreases absorption of intestinal fluids, such as nonabsorbable carbohydrates (lactulose, sorbitol) and water and electrolytes magnesium salts in laxatives and antacids. Lactose intolerance and malabsorption Fasting does not alter stool volume syndromes (e.g., celiac sprue - the inability to properly digest gluten, steatorrhea from Osmotic fat malabsorption in chronic pancreatitis) often result in osmotic diarrhea. Water and Poorly absorbed substances cause fluid and elec- trolytes into the lumen electrolytes move into the intestinal lumen to adjust to plasma osmolality in response Fasting ceases osmotic diarrhea to the movement of poorly absorbed solutes through the intestines. Unlike secretory Exudative diarrhea, osmotic diarrhea ceases with fasting. Inflammatory diseases discharge mucus, serum proteins, and blood into the gut Exudative Diarrhea Affects absorptive, secretory, or motility functions Exudative diarrhea results from direct damage to the intestinal mucosal lining or Altered Motility / Dysmotility Produces diarrhea by: brush border. Inflammatory bowel disease or infection can lead to discharge of mucus 1. reduction in contact time in small intestine and exudate such as white blood cells, blood, and/or serum proteins into the gut. 2. premature emptying of the colon Large stool volumes result from the effects of exudative diarrhea on GI absorption, 3. bacterial growth secretion, and motility. Stool volume does not change with fasting. Integrated Pharmacotherapy 2 7 Irritable Bowel Syndrome, Diarrhea, and Constipation Dysmotility Diarrhea Dysmotility diarrhea, or altered intestinal motility, results in decreased transit time in the small intestine, premature emptying of the colon, and bacterial overgrowth. This can cause inadequate absorption of fluids, electrolytes, and nutrients. Dysmotility is often caused by surgical resection of the intestine or prokinetic drugs such as metoclopramide (Reglan®), which increases the frequency of contractions in the small intestine. As with osmotic diarrhea, dysmotility diarrhea ceases with fasting. Constipation It is thought that constipation is a symptom of an underlying disease or problem Clinical Presentation of IBS including disorders of the GI tract (irritable bowel syndrome or diverticulitis), Signs and symptoms metabolic disorders (diabetes), or endocrine disorders (hypothyroidism). A Lower abdominal pain low fiber diet and/or medications (e.g., opioids) can contribute to constipation. Abdominal bloating and distension For a more comprehensive list of possible causes of constipation including Diarrhea symptoms, >3 stools per day medications, refer to Fabel PH, Shealy KM. Diarrhea, Constipation, and Irritable Extreme urgency Bowel Syndrome. In: DiPiro JT, Talbert RL, Yee GC, et. al. Pharmacotherapy: A Passage of mucus Pathophysiologic Approach, 11th Ed; 2020. Constipation symptoms, 50 years diarrhea and constipation (IBS-M, or mixed), or unclassified (IBS-U). IBS-D and Fever IBS-M tend to be more prevalent than IBS-C. Nocturnal symptoms Alarm symptoms (bottom right) are symptoms that may indicate an underlying or Blood in stools more serious organic condition that requires further gastroenterology investigation. Iron deficiency anemia Weight loss > 10% of body weight For example, patients with a subsequent diagnosis of celiac diagnosis, colitis, Profuse or large volume of diarrhea inflammatory bowel disease, and colorectal cancer may present with similar GI Family history of celiac sprue, inflammatory bowel disease, or symptoms to IBS. Routine serologic testing for celiac disease is recommended for colorectal cancer IBS-D and IBS-M. In addition, lactose breath testing may be considered in patients Physical Examination where lactose intolerance is a concern. Fever Fecal blood GOALS OF THERAPY Organomegaly Jaundice The goals of treatment for diarrhea are dietary management (such as avoidance Positive physical findings such as peritoneal signs or focal of solid foods, dairy, and caffeine), prevention of excessive disturbances in water, abdominal tenderness electrolyte, and acid-base imbalances, symptom relief, and the treatment of Adapted from Moynihan NT, et al. How do you spell relief for irritable bowel underlying causes of diarrhea (especially medications), if possible. syndrome? J Fam Pract. 2008 Feb:57(2):100-8. Integrated Pharmacotherapy 2 8 Irritable Bowel Syndrome, Diarrhea, and Constipation The goals of treatment for constipation are dietary management (such as increasing fiber and water intake, exercise, regular toileting to promote regularity, symptom relief, and treating underlying causes of constipation (such as medications or medical conditions) if possible. For IBS, the goals of therapy include symptom relief and minimizing interference with daily functioning. A multimodal approach is used, which includes dietary modifications, over the counter medications, and prescription medications. Among the medications used to manage to various forms of IBS are bulk-forming laxatives, antispasmodic agents, antidiarrheal agents, serotonin antagonists, psychotherapeutic counseling, and antidepressants. Symptom improvement is often a slow and ongoing process, and may not necessarily result in complete resolution in some cases. NONPHARMACOTHERAPY AND COMPLEMENTARY AND ALTERNATIVE MEDICINE There are several nonpharmacologic approaches that may have beneficial effects in managing IBS. Up to 60% of patients report that certain foods exacerbate their IBS symptoms, however, this has not been rigorously studied. There is a lack of objective evidence to constitute a conclusive list of foods. A food diary may be helpful in certain situations. If foods are identified as exacerbating symptoms, then exclusion diets may be helpful in those situations. Some of these foods may include raw fruits and vegetables such as broccoli, cauliflower, and cabbage; high fat or spicy foods; caffeinated products such as coffee and chocolate; alcoholic, or carbonated beverages; sweeteners such as fructose or sorbitol; wheat-containing products; beans; and dairy/lactose products. Trials have been mixed regarding food allergy testing and exclusion diets for IBS, and their routine use is not recommended. Food intolerance and hypersensitivity have been studied, although other mechanisms are proposed to affect IBS symptoms. Special diets have recently been evaluated and have shown some promise in the management of IBS, including a gluten-free diet and low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet. FODMAPs are short-chain carbohydrates (specifically sugars) that are poorly absorbed in the small intestine and rapidly fermented by bacteria in the gut, leading to gas, distention, and typically diarrhea through an osmotic action. The American College of Gastroenterology (ACG) recommends a limited trial of a low FODMAP diet in patients with IBS to improve global symptoms. Fiber supplementation can be effective for some patients with IBS in improving global symptoms. Recent evidence in a systematic review and meta-analysis published in 2014 demonstrated greater symptom relief with soluble fiber supplementation such as psyllium, but not with insoluble fiber such as wheat bran. Soluble fiber attracts water and forms a gel-like substance, thus slowing digestion. This can be helpful for patients with diarrhea. Examples of soluble fiber in foods include oats, beans, apples, peas, carrots, barley and citrus fruits. Soluble fiber is also found in over the counter preparations such as methylcellulose (Citrucel®), wheat dextrim (Benefiber®), and psyllium husk (Metamucil® contains 70% soluble fiber). Insoluble fiber may exacerbate IBS symptoms, including bloating and abdominal discomfort. Wheat bran supplementation led to a higher dropout rate compared to psyllium. Insoluble fiber adds bulk to stool and helps food pass through the stomach and intestines more quickly, which may be helpful for some individuals with constipation. Insoluble fiber is available as over the counter calcium polycarbophil (FiberCon®), as well as whole wheat flour, wheat bran, nuts, brown rice, cauliflower, green beans, and potatoes. ACG recommends soluble fiber (and not insoluble fiber) to treat global IBS symptoms. There is growing interest in the role of complementary and alternative medicines for the management of IBS symptoms. Efficacy with most complementary and alternative medicines are based on preliminary studies and warrant further study before recommending to patients with IBS. Peppermint (Mentha piperita) oil is thought to have antispasmodic activity by relaxing GI smooth muscle. and blockade of calcium channels. Studies suggest peppermint oil may be helpful reducing global IBS symptoms, including abdominal pain, bloating, flatulence, and diarrhea. Precautions for peppermint include the exacerbation of heartburn and use in pregnant or breastfeeding women (peppermint may decrease milk production). Enteric-coated capsules may help reduce heartburn in some patients by preventing dissolution in the stomach. Patients with IBS-D can consider taking 1 to 2 capsules of 0.2 to 0.4 mL peppermint oil three times daily before meals. Peppermint may increase blood levels of felodipine, simvastatin, cyclosporine, and 5-fluorouracil. The ACG suggests peppermint to provide relief of global IBS symptoms. Fennel seed oil and fennel tea are thought to be helpful for digestion, however, more studies are necessary before recommending supplementation to patients with IBS. Fennel can cause serious allergic reactions and should not be used in patients with diabetes or epilepsy, or in pregnant or breastfeeding women, infants, or children. Artichoke leaf extract (Hepar-SL forte) decreased abdominal pain and cramping, bloating, flatulence, and constipation associated with IBS after 6 weeks of treatment in a preliminary study. A different artichoke leaf extract (Cynara SL Artichoke Extract) demonstrated a reduction in IBS symptom incidence by 26% in patients with dyspepsia in a preliminary, open-label study. The trials used 320 to 640 mg artichoke leaf extract once daily. Clown’s mustard plant (contained in a combination product, Iberogast) may help dyspepsia by decreasing peristaltic movement. Sangre de grado is an herb contained in SB Normal Stool Formula promoted to manage diarrhea, but reliable evidence is lacking. Melatonin is also being studied for patients with IBS and insomnia. Preliminary results are promising. One study of melatonin 3 mg at bedtime for 2 weeks may improve sleep and abdominal pain, but not constipation, diarrhea, or bloating. Another study of melatonin 3 mg at bedtime for 8 weeks showed decreased severity and frequency of pain, decreased bloating, improved bowel habits, decreased extracolonic symptoms such as headache, heartburn and nausea, and overall improved quality of life. Integrated Pharmacotherapy 2 9 Irritable Bowel Syndrome, Diarrhea, and Constipation Probiotics to restore the normal intestinal flora and aid in digestion have been studied in patients with IBS. Some probiotics appear promising for IBS based on preliminary trials. A systematic review evaluated 19 randomized controlled trials of probiotics including Lactobacillus, Bifidobacterium, and Streptococcus. For global IBS symptoms, a combination product demonstrated significance in improving IBS symptoms, a trend towards improving IBS symptoms with Bifidobacterium, and no significant effect with Lactobacillus. The combination probiotic that demonstrated efficacy is VSL #3, which contains viable lyophylized (freeze-dried) bacteria species including Lactobacillus, Bifidobacterium, and Streptococcus. Bifidobacterium infantis 35624 (Align or Bifantis) one billion cells daily in a malted milk drink for 8 weeks may improve symptoms within one week, including abdominal pain, bloating, and constipation. Lactobacillus GG (Culterelle) and Lactobacillus salivarius did not demonstrate a significant improvement in IBS symptoms, and symptom improvement was mixed with Lactobacillus plantarum 299v (ProViva). The systematic review also discussed individual IBS symptoms, in which some improvement was reported with abdominal pain and flatulence. Probiotics were well-tolerated with no reported adverse effects or similar effects to placebo. A recent study evaluated the efficacy of a probiotic yogurt for patients with IBS-C compared to a non-probiotic yogurt and found a lack of significant differences in symptom improvement between the 2 groups. Research is ongoing to help determine the role of probiotics for IBS. A recent systematic review published in 2014 concluded that probiotics improve global symptoms, bloating, and flatulence; however, there is insufficient evidence to recommend a particular preparation or strain over another. Most recently, studies were cited with inconsistencies such as multiple types and strains of probiotics, small studies, lack of rigorous trials based on FDA endpoints, and inconsistent benefits. In 2020, the ACG suggested against probiotics for the treatment of global IBS symptoms. Patients with IBS often present with anxiety or depression. These conditions can exacerbate pain and diarrhea with IBS. Psychological therapies, such as cognitive behavioral therapy, dynamic (interpersonal) psychotherapy, and hypnotherapy, have demonstrated efficacy in relieving global symptoms of IBS compared to usual care. Relaxation therapy has also been studied; however, symptom improvement was not appreciated in patients with IBS. Several other options have been evaluated, such as acupuncture, belladonna, chamomile, and ginger; however, there is insufficient or conflicting scientific evidence to support their use for IBS symptoms. Evidence demonstrating the efficacy of alternative therapy options should be viewed with caution since many of the studies suffer from small sample sizes and poor methodology. In addition, many herbal supplements lack standardization in ingredients and potency. 5-HT Modulators and THERAPEUTIC AGENTS FOR IBS, DIARRHEA, AND CONSTIPATION C hloride Channel Activators Alosetron (Lotronex®) There is a multitude of both over the counter (OTC) and prescription medications used for Route: PO (tablet) management of diarrhea and constipation. This section of Integrated Pharmacotherapy will Availability: Rx (restricted access) focus on opioids used for the treatment of diarrhea (diphenoxylate/atropine and loperamide), Tegaserod (Zelnorm®) 5-HT (serotonin) receptor modulators used for IBS-D (alosetron), and chloride channel Route: PO activators (lubiprostone) used for IBS-C. The opioids are a large class of drugs used most Availability: Rx (restricted access) often for pain management, and the pharmacology, medicinal chemistry and pharmaceutics Lubiprostone (Amitiza®) of this class of drugs will be covered in detail later in IP7: Pain Management. Likewise, Route: PO (capsule) drugs that interact with serotonin receptors are used more frequently in other disease states, Availability: Rx and these drugs will also be covered in detail later in the Integrated Pharmacotherapy series. Prucalopride (Motegrity®) The majority of laxative drugs are OTC, and these are covered in the Therapeutic Principles Route: PO (Tablet) of Self-Care course. A peptide drug with a novel mechanism of action (linaclotide) was Availability: Rx approved by the FDA in December of 2012 and will also be discussed. NHE3 Antagonists Drug Formulation, Delivery and Absorption Tenapanor (Ibsrela®) Route: PO Drug Formulation Availability: Rx All of the medications covered in this section are available as oral formulations. In the United Opioid Agonists (Opioids) States, diphenoxylate is only available in combination with atropine; this combination is Diphenoxylate / Atropine (Lomotil®) often referred to as Lomotil®, the original brand name, and is available both in solid and Route: PO (tablet and solution) liquid oral formulations. Likewise, loperamide (Imodium®) is available in solid and liquid Availability: Rx (Schedule V) oral formulations. Loperamide (Imodium®, Imodium®-AD) Drug Absorption Route: PO (capsule, tablet, chewable tablet, liquid, suspension) The opioids diphenoxylate and loperamide are both well absorbed. However, due to different Availability: Rx and OTC distribution profiles (see next section), only diphenoxylate has a potential for opioid effects in the systemic circulation (i.e., effects in addition to those in the GI tract). Lubiprostone has Miscellaneous Agents low oral bioavailability, but its site of action is at the apical (luminal) side of the intestinal Linaclotide (Linzess®) membrane and poor systemic availability is irrelevant because it doesn’t need to be absorbed Route: PO (capsule) into the systemic circulation to cause its desired effects. Availability: Rx Integrated Pharmacotherapy 2 10 Irritable Bowel Syndrome, Diarrhea, and Constipation Linaclotide (Linzess®) is a 14 amino acid peptide which is poorly absorbed; plasma levels Figure 8. Opioid receptor classification are undetectable after normal dosing. The drug acts at receptors on the luminal membrane, Opioid Receptors so poor absorption is not a concern. Linaclotide should be taken at least 30 minutes before breakfast each day. Drug Distribution, Action and Effects δ κ µ Opioid Agonists Delta Kappa Mu Opioid drugs interact with opioid receptors as full agonists, partial agonists, or antagonists. Opioid receptors are G-protein coupled receptors found in both the peripheral and central nervous system. There are three main subtypes of opioid receptors: mu, delta and kappa (Figure 8). Most therapeutically useful Figure 9. Effect of opioid receptor activation opioids produce their effect by interacting with mu receptors. This section of Integrated Presynaptic Cholinergic Neuron Pharmacotherapy will focus on the interaction of opioids with opioid receptors in the gastrointestinal tract. Opioid agonists (full and partial) produce a variety of effects in the GI tract, but most opioids are not used specifically for GI tract disorders due to their abuse potential and side effect profile. Rather, the actions of opioids on the GI tract are most often considered to Decreased ACh release from neuron be adverse effects. Throughout the GI tract, opioid nerve tracts synapse onto cholinergic ACh neurons, and the release of endogenous opioids such as leu-enkephalin and met-enkephalin X results in activation of opioid receptors on presynaptic cholinergic neurons, which ultimately Presynaptic opioid receptor acts to inhibit the release of acetylcholine (ACh) (Figure 9). Therefore, opioids have an anticholinergic effect in the GI tract. In the stomach, the decrease in acetylcholine release ACh Opioid drug results in delayed gastric emptying, which may lead to exacerbation of GERD. All opioid agonists produce a constipating effect due to a decrease in the number of propulsive Figure 10. Meperidine-like 4-phenylpiperidine peristaltic waves in the large intestine. This results in a delay in passage of bowel contents derivatives (diphenoxylate and loperamide are and increased water absorption in both the small and large intestine. antidiarrheal agents) CH3 While the family of opioid drugs contains a large number of structurally diverse compounds, O N most opioids belong to one of several chemically-similar groups. The 4-phenylpiperidine opioids include the well-known full opioid agonist meperidine (Demerol®). From this O group of opioids, two partial mu receptor agonists useful as antidiarrheal agents have been developed: loperamide and diphenoxylate (Figure 10). Loperamide (Imodium®) is a partial mu opioid receptor agonist that does not have an Meperidine abuse potential due to its lack of distribution into the CNS (the abuse potential of opioids is due to their CNS effects, such as euphoria; repeated abuse will lead to opioid addiction). Loperamide does not distribute into the CNS because it is actively pumped back into the blood when it tries to cross the blood-brain-barrier. The protein transporter responsible for this efflux is P-glycoprotein (P-gp). P-gp is found throughout the body and plays a major role in drug transport; in this case, its effect on blocking drug transit into the CNS via efflux is N O the most important determinant of the lack of abuse potential for loperamide. Accordingly, N loperamide is a rare exception in the large family of opioid drugs in that it is not scheduled as a controlled substance by the FDA. O Diphenoxylate Unlike loperamide, diphenoxylate, when taken at high doses, distributes into the CNS to (dye fen OKS i late) such a sufficient extent as to have an abuse potential. To discourage its abuse, diphenoxylate is formulated with the anticholinergic drug atropine to make the product Lomotil®. This accomplishes two things: 1) atropine discourages abuse of Lomotil® because if a patient takes an excessive amount, the atropine produces uncomfortable anticholinergic side effects (tachycardia, nausea, vomiting, confusion, dry mouth, urinary retention, sedation, constipation, decreased GI motility) and 2) the anticholinergic effect of atropine also adds to O the constipating effect of diphenoxylate (however this effect is small due to the low amount N of atropine present in recommended dosing of Lomotil®). Diphenoxylate is a weak partial HO N mu opioid agonist and essentially functions as a prodrug: following absorption into the H3C CH3 systemic circulation, diphenoxylate is rapidly metabolized by ester hydrolysis to difenoxin, Loperamide which is about five times more potent than diphenoxylate (this factor also contributes to (loe PER a mide) the abuse potential of diphenoxylate). Diphenoxylate/atropine is a schedule V controlled substance in the United States. Cl Integrated Pharmacotherapy 2 11 Irritable Bowel Syndrome, Diarrhea, and Constipation At recommended doses both loperamide and diphenoxylate/atropine have few adverse effects. Most commonly reported adverse effects are difficult to distinguish from effects associated with diarrhea (e.g., abdominal pain). As mentioned above, with excessive doses diphenoxylate/atropine will produce adverse effects related to 1) excessive opioid effects on the CNS (e.g., euphoria, confusion, respiratory depression) and 2) excessive anticholinergic effects on the autonomic nervous system. Figure 11. Alosetron and Serotonin 5-HT Receptor Modulators H 5-hydroxytryptamine (serotonin; 5-HT) is a neurotransmitter found throughout the body. Despite its N most familiar and well established roles in the CNS, over 90% of 5-HT is located in the enterochromaffin cells of the GI tract, where it plays an important role in regulating GI function via interactions with HO 5-HT receptors. Enterochromaffin cells are secretory cells found in the endothelium of the intestinal lumen. These cells sense chemical and physical stimuli in the gut following ingestion of a meal and, Serotonin (5HT) NH2 in response, secrete serotonin. In the intestines, serotonin acts primarily in a costimulatory role on cholinergic enteric neurons. It stimulates muscle contraction as well as the secretion of ions, mucus, and fluid into the intestinal lumen by acting on serotonin type 3 (5-HT3) and serotonin type 4 (5- N HT4) receptors. Serotonin has also been implicated in complex signaling pathways throughout the ENS (including effects on afferent nerves signaling to the CNS) which lead to sensory transmission and the experience of abdominal pain. Investigations have determined that patients with IBS-related H N N diarrhea have elevated postprandial (after a meal) levels of serotonin when compared to individuals O without IBS. While these observations do not directly implicate serotonin as a causative agent in the N development of IBS, 5HT3 and 5HT4 have been found to be fruitful targets for alleviating symptoms Alosetron of IBS. In summary, blocking 5-HT3 receptors has a constipating effect, while activation of 5-HT4 (a LOE se tron) receptors helps relieve constipation. Alosetron is a chemical analog of serotonin (Figure 11) that is designed Figure 12. Tegaserod & Prucalopride to fit into 5-HT receptors in the place of serotonin. This is an example H of a common medicinal chemistry drug design strategy: creating a drug N by synthesizing a chemical analog of the endogenous receptor ligand. Alosetron, however, does not fit into all 5-HT receptors; rather, it is a NH selective antagonist at 5-HT3 receptors, a subtype in the 5-HT receptor O N family. Alosetron decreases GI motility, slows transit of material through Tegaserod N N the GI tract, and promotes absorption of fluid from the GI tract into the (teg a SER od) H H body. Collectively, these pharmacologic effects produce a constipating effect. Alosetron is therefore indicated for IBS-D. Alosetron has been associated with serious adverse effects, such as ischemic colitis, which are related to its constipating actions. Ischemia refers to O N O inadequate blood supply which, in this case, results in inflammation of the large intestine, or colitis. These adverse reactions have occasionally led Cl to the need for surgical intervention and have even resulted in death in N H some cases. In fact, alosetron was withdrawn temporarily from the market in the United States due to these effects. Currently, alosetron access is H2N Prucalopride O (proo KAL oh pride) limited to prescribers who have enrolled in the manufacturer’s prescribing program. Patients should be counseled to watch for signs of ischemic colitis (abdominal pain, bloody stools) and for excessive constipation. Alosetron must be dispensed with a Medication Guide as required by the FDA. Figure 13. Lubiprostone Tegaserod (Zelnorm®; Figure 12) is a partial 5-HT4 receptor agonist useful in the O treatment of IBS-C. Interestingly, it was withdrawn from the United States drug market OH in 2007 due to increased risk of myocardial infarction, stroke, and unstable angina. However, tegaserod has recently been reevaluated and is intended to return to the Prostanoic Acid market for use in women under 65 without CV disease and with no more than one CV risk factor. HO O H Common adverse effects of tegaserod include headache, abdominal pain, nausea, F diarrhea, flatulence, dyspepsia, and dizziness. Tegaserod is contraindicated in patients F O OH with a history of myocardial infarction, stroke, transient ischemic attack, or angina; H O history of ischemic colitis or other forms of intestinal ischemia; severe renal impairment Lubiprostone (eGFR< 15 mL/min/1.73 m2) or end-stage renal disease; moderate or severe hepatic (loo bi PROS tone) impairment (Child-Pugh B or C); history of bowel obstruction, symptomatic gallbladder Lubiprostone is similar to the chemical foundation of disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions. prostaglandins, but does not bind to prostaglandin receptors Integrated Pharmacotherapy 2 12 Irritable Bowel Syndrome, Diarrhea, and Constipation Like tegaserod, prucalopride (Motegrity®; Figure 12 on page 12) is Figure 14. Tenapanor a 5-HT4 receptor agonist indicated for the relief of chronic idiopathic constipation. Prucalopride is rapidly absorbed with > 90% bioavailability. It is primarily excreted unchanged in the urine (84.2%) and the feces (13.3%). The most common adverse effects reported with prucalopride include headache, abdominal pain, nausea, diarrhea, abdominal distention, dizziness, vomiting, flatulence, and fatigue. Prucalopride is contraindicated in patients with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory Tenapanor conditions of the intestinal tract such as Crohn’s disease, ulcerative colitis, (ten A pa nor) and toxic megacolon/ megarectum. Chloride Channel Activators Lubiprostone, a member of a new class of drugs called chloride channel activators, is a chemical derivative of prostanoic acid, a 20-carbon fatty acid skeleton that is the chemical foundation for all of the endogenous prostaglandins (fatty acid derivatives that produce a variety of effects throughout the body; Figure 13 on page 12). Lubiprostone is most similar to prostaglandin E1; however, lubiprostone is different enough from endogenous prostaglandins such that it does not bind with prostaglandin receptors. Lubiprostone activates a specific type of chloride channels (ClC-2) on the apical (lumen) side of the gastrointestinal epithelial cells, resulting in efflux of chloride ions into the gastrointestinal tract. This in turn results in retention of fluid in the gastrointestinal tract, softening of fecal matter, and relief of constipation. Common side effects of lubiprostone include nausea, diarrhea, and abdominal pain. Lubiprostone is used at higher doses for chronic idiopathic constipation, while smaller doses are employed for treatment of IBS-C. Sodium Channel Inhibitors Tenapanor (Ibsrela®; Figure 14) is a minimally absorbed small molecule inhibitor of the sodium-hydrogen exchanger 3 (NHE3) indicated for the treatment of IBS-C in adults. Inhibition of the exchanger prevents the absorption of sodium from the GI tract which results in an osmotic gradient and a net flow of water into the gut lumen. While the NHE3 transporter is also found in the kidneys, where it reabsorbs sodium from the tubular filtrate in exchange for a proton, tenapanor is poorly absorbed and thus is only active on intestinal NHE3. Dehydration is a particular risk when using tenapanor. Patients with known or suspected mechanical gastrointestinal obstruction, and patients less than six years of age are contraindicated from taking Tenapanor due to severe dehydration. Reported adverse events with the use of Tenapanor include diarrhea, abdominal distension, flatulence, and dizziness. If patients do experience diarrhea, suspend dosing and rehydrate. Prescription Osmotic Agents Lactitol (Pizensey®) is an osmotic laxative indicated for the treatment of chronic idiopathic constipation OH (CIC) in adults. A simple carbohydrate, lactitol wss originally used as a sweetening agent in food before HO being approved by the FDA for CIC in 2020. The mechanism of action of lactitol is similar to that of OH HO H soluble fiber in it is incapable of being absorbed by the GI tract and thus creates an osmotic gradient O O H whereby it draws water out of the body and into the gut. OH H OH As lactitol is not readily absorbed from the gut, it has a favorable adverse effects profile. Generally, on HO H account of its mechanism of action, lactitol can decrease the absorption of other medications by flushing OH them through the GI tract more rapidly than would otherwise be the case. Therefore, lactitol should be OH taken two hours before or two hours after other medications. It is contraindicated in patients who have Lactitol a mechanical GI obstruction (known or suspected) and in patients with galactosemia. Miscellaneous Gastrointestinal Agents Linaclotide (Linzess®; Figure 15 on page 14) and plecanatide (TrulanceTM; similar in structure to linaclotide) and their active metabolites are peptides which bind and agonize guanylate cyclase-C (GC-C) on the luminal surface of intestinal epithelium. Intracellular and extracellular cyclic guanosine monophosphate (cGMP) concentrations are subsequently increased, resulting in the activation of cGMP-dependent protein kinase II (PKG-II; Figure 16). Once activated, PKG-II phosphorylates, and thereby regulates, the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel protein colocalized with PKG-II at the apical surface of intestinal epithelial cells. The activated CFTR channel mediates chloride and bicarbonate secretion into the intestinal lumen, which results in an osmotic gradient and an outward flow of water. Intestinal fluid increases and transit time is decreased. Extracellular cGMP may also decrease visceral pain by reducing pain-sensing nerve activity through its action on afferent pain pathways (bottom of Figure 16). Integrated Pharmacotherapy 2 13 Irritable Bowel Syndrome, Diarrhea, and Constipation In adults, linaclotide and plecanatide are associated with a low incidence of Figure1. Figure 15.Linaclotide Linaclotide adverse GI effects, including diarrhea, flatulence, vomiting, abdominal pain, and incontinence. Neither drug is absorbed out of the gut so no systemic adverse events are expected. Both agents also carry a black-box warning restricting their use in children on account of an increased risk of dehydration: Use is contraindicated in pediatric patients ≤6 years of age. Avoid use in pediatric patients 6-17 years of age. Deaths observed in young juvenile animals during nonclinical studies Managing Symptoms versus Treating Disease In general, it is ideal to treat the underlying disease with drug therapy rather than simply managing disease symptoms. In the case of IBS, unfortunately, most of the available therapeutic agents target symptom management and do not directly address the underlying pathology. Opioids and lubiprostone fall into the category of managing IBS symptoms (either diarrhea or constipation). The Linaclotide administration of alosetron, on the other hand, is an attempt at modifying the (lin AK loe tide) underlying disease process by interacting with the serotonin system in the gastrointestinal tract. Drug Elimination Figure 16. Linaclotide & plecanatide mechanism of action. Loperamide undergoes extensive first-pass metabolism by N-demethylation catalyzed by CYP2C8 and CYP3A4, a factor which adds to its relatively low systemic bioavailability (about 40%). Loperamide is eliminated by a combination of CYP450 hepatic metabolism followed by fecal and renal metabolite excretion, with only 1% of the dose excreted unchanged into the urine. As mentioned above, diphenoxylate is hydrolyzed to difenoxin by ester hydrolase enzymes; difenoxin is subsequently metabolized by glucuronidation. Alosetron is extensively metabolized by CYP1A2 and to a lesser extent by 2C9, and 3A4. Alosetron and its metabolites are mainly eliminated by urinary (73%) and fecal (24%) excretion. Lubiprostone is extensively metabolized by non- CYP450 enzymes. Due to the extensive elimination of the drugs in this section by metabolism, dose adjustment in patients with compromised renal function is generally unnecessary. Linaclotide is converted in the gut to an active metabolite. Both the parent drug and the metabolite, being simple peptides, are further broken down through normal proteolytic metabolism and absorbed as nutrient amino acids. Any of the active metabolite not fully digested is excreted in the feces (3-5%). Drug Interactions The drugs presented above have not been associated with very many clinically important drug-drug interactions. The amount and effect of alosetron in the body may be increased by drugs that inhibit its metabolism. Fluvoxamine, for example, is a potent CYP1A2 inhibitor and is contraindicated for concomitant use with alosetron. CNS depressants (e.g., barbiturates, benzodiazepines, opioids) may increase the potential CNS depressant effects of diphenoxylate, but this is uncommon when diphenoxylate/atropine is taken at recommended doses. Additional Agents used in the Treatment of IBS Antispasmotics Anticholinergic agents such as dicyclomine (Bentyl®) and hyoscyamine (Levsin®) antagonize the activity of acetylcholine at muscarinic receptors on the smooth muscles of the small intestines. Blocking the activity of acetylcholine at these receptors results in an antispasmotic activity that reduces intestinal hypermotility, a common symptom of IBS. As these agents are anticholinergics, they are burdened by the common side effects associated with all drugs in this class: dry mouth, headache, dizziness, and confusion. Other Agents Note that there are several other agents listed in the clinical section of these notes beginning on page 15. The pharmacology of these will be covered in future IP units, but you are responsible for knowing how they are used in the treatment of IBS. Integrated Pharmacotherapy 2 14 Irritable Bowel Syndrome, Diarrhea, and Constipation THERAPEUTIC APPLICATIONS OF EVIDENCE-BASED MEDICINE FOR IBS, DIARRHEA, AND CONSTIPATION The management of diarrhea and constipation is covered primarily in the Therapeutic Principles of Self-Care course, as many of these medications are available over-the-counter. For your reference, Table 1 provides dose regimens for loperamide and diphenoxylate/ atropine for managing diarrhea. Dose regimens to manage IBS-D with alosetron, eluxadoline, and rifaximin and IBS-C with tegaserod and lubiprostone are provided in Table 2. Table 1. Drugs approved for diarrhea Table 2. Drugs with FDA indication for irritable bowel syndrome. Drug Dose Medication Type Mechanism of Action Adult Dosage Initial 4 mg followed by 2 mg after each Alosetron (Lotronex®) IBS-D 5-HT3 Receptor Antagonist 0.5 to 1 mg BID Loperamide (Imodium®) loose stool, up to 16 mg per day 6 mg BID before Tegaserod (Zelnorm®) IBS-C 5-HT4 Receptor Agonist Diphenoxylate/Atropine 5 mg four times a day, up to 20 mg per meals (Lomotil®) day of diphenoxylate Lubiprostone (Amitiza®) IBS-C Chloride Channel Activator 8 mcg BID with food 290 mcg daily 30 Guanylate cyclase-C Linaclotide (Linzess®) IBS-C minutes before Agonist breakfast Guanylate cyclase-C Plecanatide (Trulance®) IBS-C 3 mg PO daily Agonist Eluxadoline (Viberzi®) IBS-D mu opioid receptor agonist 100mg twice daily Rifaximin (Xifaxan®) IBS-D non-absorbable antibiotic 550mg 3 times/day All Patients with IBS The management of IBS discussed here is primarily based on the 2020 American College of Gastroenterology (ACG) Clinical Guideline: Management of Irritable Bowel Syndrome. Factors which may exacerbate IBS symptoms should be addressed, such as psychological issues, stress, and food intolerance or allergies (such as common offenders milk, eggs, and wheat). Therefore, a thorough patient history should be obtained to identify potential exacerbating factors. General treatment options for IBS are discussed in detail below. Antispasmodics, such as dicyclomine (Bentyl®) and hyoscyamine (Levsin®), are commonly used to treat IBS symptoms. Antispasmodics are believed to improve global IBS symptoms, including abdominal pain. Antispasmodics relax intestinal smooth muscle, resulting in reduced GI motility. Antispasmodics were previously recommended but have fallen out of favor, mainly due to older, poor quality studies. These studies suggested an improvement in global IBS symptoms, however, they had inconsistent standardized enrollment criteria, trial designs and endpoints, as well as small sample sizes. In addition, antispasmodics have the potential for anticholinergic effects (which may be more useful with IBS-D). Some patients may benefit from short-term use to relieve abdominal pain and discomfort in patients with IBS, however, evidence for long-term use is limited. As such, the ACG recommend against the use of antispasmodics for the treatment of global IBS symptoms. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been considered in the management of IBS. As neuromodulators acting on norepinephrine and dopaminergic receptors, TCAs are believed to improve visceral pain and central pain - which may improve abdominal pain associated with IBS. Examples of TCAs include desipramine (Norpramin®), nortriptyline (Pamelor®), and amitriptyline (Elavil®). In addition, because of its anticholinergic effects, TCAs may slow intestinal transit and improve IBS-D for some patients. As antidepressants, TCAs may also help treat comorbid depression. With its potential benefits comes the increased risk for anticholinergic adverse effects, which are significantly higher compared to placebo. Anticholinergic adverse effects include drowsiness, dry mouth, constipation, urinary retention, and cardiac arrhythmias. The ACG recommends TCAs to treat the global symptoms of IBS. Caution is advised due to patient tolerance to TCAs. SSRIs, such as fluoxetine (Prozac®), paroxetine (Paxil®), and citalopram (Celexa®), are generally better tolerated than TCAs. Because of a mild prokinetic effect in some patients, a small fraction may benefit from possible increase in GI motility (as with IBS-C); however, the evidence is weak and most patients may be taking SSRIs for comorbid depression and/or anxiety primarily. Because the evidence is not as strong for SSRIs, the ACG does not recommend SSRIs in relieving global IBS symptoms. As patients with IBS may present with concurrent depression or anxiety, TCAs or SSRIs may provide additional benefit in these patients (especially when combined with psychotherapy). Antidepressants will be covered in detail in the “Major Depressive Disorders” unit of Integrated Pharmacotherapy 3. Eliminating certain foods or treating underlying psychological or physical disorders may improve symptoms and reduce the need for further treatment, particularly when IBS symptoms are minor. However, in the majority of cases, pharmacotherapy is required for symptom management. The pharmacologic management of IBS varies depending on if the patient primarily has IBS-C or IBS-D. Constipation-Predominant IBS When considering treatment for IBS-C, soluble fiber such as psyllium may provide overall symptom improvement and improve constipation. To minimize the unwanted side effects of gas and bloating, dietary fiber should be introduced gradually as tolerated. Integrated Pharmacotherapy 2 15 Irritable Bowel Syndrome, Diarrhea, and Constipation An osmotic laxative, such as polyethylene glycol or PEG (MiraLax®), has its main role in treating chronic idiopathic constipation (CIC), with much of the evidence for an increase in frequency of bowel movements. However, in patients with IBS-C, there is no evidence that PEG improves abdominal pain and global IBS symptoms. For instance, one small study in adolescents with IBS-C demonstrated an increase in stool frequency (number of bowel movements per week), but no improvement in abdominal pain. Osmotic laxatives may contribute to gas, distention, and abdominal discomfort. As such, the ACG suggested against the use of PEG products to relieve global IBS symptoms in patients with IBS-C Stimulant laxatives, sometimes referred to as natural or vegetable laxatives, can be effective for patients with CIC. These anthraquinone laxatives are generally believed to directly stimulate colonic smooth muscle, and more recently have been found to increase fluid secretion into the bowel. Senna or sennosides (Senokot®) is available over the counter and is derived from the senna plant. Other natural stimulant laxatives which are available as dietary supplements include aloe, cascara sagrada, European buckthorn, and rhubarb. Stimulant laxatives are generally not recommended long-term and were reclassified from FDA Category I (generally recognized as safe and effective) to Category III (further testing is required) in 1998. Bisacodyl (Dulcolax®) is also available over the counter but is derived from diphenylmethane. Stimulant laxatives can cause significant abdominal cramping and diarrhea. Nutrient malabsorption and lost of electrolytes is also a concern with long-term use. Note that the evidence for laxatives in IBS is limited. Linaclotide (Linzess®) is a guanylate cyclase-C agonist that is indicated in adults for the treatment of IBS-C at 290 mcg orally daily and chronic idiopathic constipation (CIC) at 145 mcg orally daily, to be taken on an empty stomach at least 30 minutes prior to the first meal of the day. FDA approval was based on two randomized, double-blind, placebo-controlled trials studied mostly in white females. Linaclotide was more effective than placebo in reducing abdominal pain and improving frequency of bowel movements and global symptoms of IBS. Linaclotide carries a black box warning and is contraindicated in pediatric patients up to 6 years old, and use is recommended to be avoided in pediatric patients age 6-17 years due to deaths from dehydration in young juvenile mice. Adverse events were similar to placebo, though linaclotide caused significantly more diarrhea, flatulence, abdominal pain, and abdominal distention in clinical trials. The ACG recommends the use of guanylate cyclase activators to treat global IBS-C symptoms. Lubiprostone (Amitiza®) is a chloride channel activator that is FDA-approved for the treatment of IBS-C in adult women, CIC, and opioid- induced constipation (OIC) in adults with chronic, non-cancer pain. In 2 large clinical trials, lubiprostone was shown to improve global IBS-C symptoms, as well as individual symptoms of abdominal pain, stool frequency, straining, and constipation severity. Lubiprostone is prescribed at 8 mcg orally twice daily with food and water for IBS-C and at the higher dose of 24 mcg orally twice daily with food and water for CIC and OIC. The adverse effects of nausea, diarrhea, and abdominal pain appear to be less frequent at the decreased dosage required to treat IBS-C. To minimize nausea with lubiprostone, it is recommended to be taken with a meal and 8 ounces of water. Common adverse effects at the lower dose for IBS-C include nausea, diarrhea, and abdominal pain, Unique to lubiprostone, patients may experience dyspnea within an hour of taking the first dose, generally resolving within 3 hours; dyspnea may recur with repeated dosing. The AGA and ACG suggest using lubiprostone as a treatment option for IBS-C. The ACG recommends the use of chloride channel activators to treat global IBS-C symptoms. Tegaserod, a 5-HT4 receptor agonist, has been shown to be effective in improving global IBS-C symptoms in women (improvement in abdominal discomfort, bloating, and constipation) and in patients with IBS-M, compared to placebo. Tegaserod was withdrawn from the U.S. market in 2007 due to concerns for cardiovascular (CV) events. Tegaserod later became available under a restricted treatment investigational new drug (T-IND) protocol. Subsequently in 2008, the manufacturer withdrew the T-IND, but agreed to supply tegaserod in emergency situations through special requests made to the FDA. As a result, tegaserod was no longer recommended or used in routine practice. Analyses have shown that a small group of patients with CV ischemic events had at least 1 to 2 CV risk factors, and subsequent analyses found no evidence of increased proarrhythmic risk or platelet aggregation among patients. In April 2019, the FDA approved tegaserod for the treatment of adult women less than 65 years of age with IBS-C. Although there is still an increased risk for cardiovascular (CV) events, tegaserod can now be prescribed without a REMS program. Additional analyses found no evidence of increased proarrhythmic risk or platelet aggregation within these studies. In addition to potential CV effects, patients should be advised to report mood changes and any suicidal thoughts due to its serotonergic effects. The ACG suggests the 5-HT4 agonist tegaserod be used to treat IBS-C symptoms in women younger than 65 years with 1 or less CV risk factors who have not adequately responded to 1st line medications such as chloride channel activators or guanylate cyclase activators. Tenapanor (Ibsrela®) was approved by the FDA in September 2019 for the treatment of IBS-C in adults. Based on two phase 3 trials (12 weeks and 26 weeks), individuals with IBS-C demonstrated modest improvement in abdominal pain and constipation. Tenapanor is contraindicated in patients younger than 6 years old due to a study demonstrating increased risk of death due to dehydration in juvenile rats. In 2021, tenapanor is not yet available in the U.S. Diarrhea-Predominant IBS The initial management of IBS-D requires a thorough evaluation of underlying causes of diarrhea, including foods, medications, and underlying medical conditions. Exacerbating factors should be avoided or eliminated, if feasible. Avoidance of certain foods may relieve IBS symptom in some patients. These foods can include dairy products if lactose intolerance is Integrated Pharmacotherapy 2 16 Irritable Bowel Syndrome, Diarrhea, and Constipation suspected, alcohol, chocolate, or caffeinated beverages, large meals, and/or high-fat meals. In addition, sweeteners (especially products containing artificial sweeteners) should be avoided due to their ability to produce a laxative effect in some patients. Avoidance of solid foods is recommended for severe diarrhea. The elimination of potentially offensive foods should be monitored to see if there is any improvement in diarrhea symptoms. Adequate hydration and electrolyte replacement is essential for chronic diarrhea. Loperamide (Imodium®) is often used to manage IBS-D due to its low cost, wide availability, and minimal adverse effects. The treatment dosage for acute diarrhea is typically 4 mg with the initial loose bowel movement, followed by 2 mg after each loose stool (maximum 16 mg/day), and a typical dose range for chronic diarrhea is 4-8 mg/day in divided doses. The ACG acknowledged its efficacy as an antidiarrheal, but stated there was insufficient evidence to recommend its use in treating the global symptoms of IBS. Due to the paucity of data, the American Gastroenterological Association (AGA) suggests its place in therapy as an adjunct to other therapies for IBS-D. Both guidelines do not address the role of diphenoxylate/atropine in treating IBS-D. In addition to symptom relief, the management of IBS is targeted at the suspected pathophysiologic dysfunction associated with IBS. The 5-HT3 receptor antagonist, alosetron (Lotronex®), has demonstrated effectiveness in treating abdominal pain and global symptoms in women with IBS-D. Alosetron is approved only in women with severe IBS-D, including chronic IBS symptoms generally lasting 6 months or longer (excluding anatomic or biochemical abnormalities of the GI tract) and not responded adequately to conventional therapy. The manufacturer defines severe IBS-D as diarrhea plus IBS is defined 1 or more of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, or disability or restriction of daily activities due to IBS. Concerns of a link between the use of alosetron and severe constipation and ischemic colitis resulted in its withdrawal from the U.S. market in 2000. Subsequently, alosetron was reintroduced in 2002 under a limited use, risk management program (risk evaluation and mitigation strategy, or REMS, program since 2010) for patients with severe IBS-D, in whom standard therapy has failed. The ACG recommends that alosetron be used to relieve global IBS-D symptoms in women with severe symptoms who have failed conventional therapy. In the past, antibiotics were used off-label for the management of IBS symptoms. In May 2015, rifaximin (Xifaxan®) received FDA approval for the treatment of IBS-D. Rifaximin is a nonabsorbed rifamycin antibacterial that is also approved for the treatment of travelers’ diarrhe