Journal of Parenteral and Enteral Nutrition http://pen.sagepub.com/
Pharmacologic Management of Diarrhea in Patients With Short Bowel Syndrome Vanessa J. Kumpf JPEN J Parenter Enteral Nutr 2014 38: 38S originally published online 24 January 2014 DOI: 10.1177/0148607113520618 The online version of this article can be found at: http://pen.sagepub.com/content/38/1_suppl/38S
Published by: http://www.sagepublications.com
On behalf of:
The American Society for Parenteral & Enteral Nutrition
Additional services and information for Journal of Parenteral and Enteral Nutrition can be found at: Email Alerts: http://pen.sagepub.com/cgi/alerts Subscriptions: http://pen.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Apr 22, 2014 OnlineFirst Version of Record - Jan 24, 2014 What is This?
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520618
research-article2014
PENXXX10.1177/0148607113520618Journal of Parenteral and Enteral NutritionKumpf
Invited Review
Pharmacologic Management of Diarrhea in Patients With Short Bowel Syndrome Vanessa J. Kumpf, PharmD, BCNSP1
Journal of Parenteral and Enteral Nutrition Volume 38 Supplement 1 May 2014 38S–44S © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0148607113520618 jpen.sagepub.com hosted at online.sagepub.com
Abstract Diarrhea associated with short bowel syndrome (SBS) can have multiple etiologies, including accelerated intestinal transit, gastric acid hypersecretion, intestinal bacterial overgrowth, and malabsorption of fats and bile salts. As a result, patients may need multiple medications to effectively control fecal output. The armamentarium of antidiarrheal drugs includes antimotility agents, antisecretory drugs, antibiotics and probiotics, bile acid–binding resins, and pancreatic enzymes. An antidiarrheal regimen must be individualized for each patient and should be developed using a methodical, stepwise approach. Treatment should be initiated with a single first-line medication at the low end of its dosing range. Dosage and/or dosing frequency can then be slowly escalated to achieve maximal effect while minimizing adverse events. If diarrhea remains poorly controlled, additional agents can be incorporated sequentially. If modification of the regimen is required, a single medication should be altered or exchanged at a time. After each adjustment of the regimen, sufficient time should be permitted to fully assess response (≥3–5 days) before initiating additional changes. SBS-associated malabsorption is a major obstacle to optimization of an antidiarrheal regimen because drug absorption is impaired. Patients may benefit from high dosages and/or frequent dosing intervals, liquid preparations, or nonoral routes of drug delivery. Although the diarrhea associated with SBS can be debilitating, effective pharmaceutical management has the potential to substantially improve health outcomes and quality of life for these patients. (JPEN J Parenter Enteral Nutr. 2014;38(suppl 1):38S-44S)
Keywords gastroenterology; research and diseases; adult; life cycle; probiotics; home nutrition support; nutrition; internal medicine
Management of short bowel syndrome (SBS) focuses on replacement of fluid and nutrient losses, achieving or maintaining adequate weight, and controlling diarrhea. Multiple factors contribute to diarrhea in patients with SBS, including accelerated intestinal transit, increased gastrointestinal (GI) secretions, bacterial overgrowth, and malabsorption of fats and bile salts. Diarrhea can negatively affect health outcomes for patients with SBS. For example, diarrhea leaves patients at increased risk of dehydration, micronutrient deficiencies, and weight loss. Furthermore, quality of life can be diminished by severe diarrhea associated with SBS. Patients have expressed fears related to eating because of probable increased stool output and reluctance to leave home because of possible fecal incontinence.1,2 In fact, patients with ostomies may face fewer disruptions to daily life than patients with colon-incontinuity because of reduced bathroom dependency.3 Both dietary manipulation and pharmacologic management of diarrhea have the potential to substantially improve overall health and quality of life for this patient population. This article focuses on pharmacologic management of diarrhea. Please refer to other resources for a discussion of diet manipulation for diarrhea reduction in patients with SBS.4-6
Antimotility Agents A primary cause of diarrhea in patients with SBS is increased intestinal motility, resulting in accelerated small bowel transit
time.7 The etiology underlying increased intestinal motility in SBS is unclear but has been assumed to be related to the loss of an inhibitor of intestinal motility normally released from the distal GI tract. Indeed, patients with end jejunostomy experience more rapid intestinal transit of liquids than patients with colon-in-continuity, perhaps because of lower plasma levels of peptide YY, glucagon-like peptide 1, and/or glucagon-like peptide 2.8-12 Accelerated intestinal motility is typically treated with opioids or opioid receptor agonists that inhibit contraction of intestinal smooth muscles. The resulting increase in intestinal From the 1Vanderbilt University Medical Center, Nashville, Tennessee. Financial disclosure: The publication of the supplement in which this article appears is supported by an educational grant from NPS Pharmaceuticals, Inc (Bedminster, NJ). Funding for medical writing assistance was provided by NPS Pharmaceuticals, Inc. V.J.K. has served as a consultant for NPS Pharmaceuticals, Inc. No financial compensation was provided to V.J.K. for the preparation of this work. Received for publication October 30, 2013; accepted for publication December 30, 2013. Corresponding Author: Vanessa J. Kumpf, PharmD, BCNSP, Vanderbilt University Medical Center, 1211 21st Ave S, 514 Medical Arts Bldg, Nashville, TN 37232, USA. Email: [email protected]
Downloaded from pen.sagepub.com at TEMPLE UNIV on October 15, 2014
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Figure 1. Treatment algorithm for the pharmacologic management of diarrhea associated with short bowel syndrome. H2 = histamine type-2 receptor.
transit time allows for greater nutrient absorption.13,14 Loperamide and diphenoxylate-atropine are typically the firstline choices for antimotility agents (Figure 1). As a peripherally restricted µ-opioid receptor agonist, loperamide does not engender undesirable central nervous system (CNS) effects, such as sedation, euphoric effects, or addiction.15 Furthermore, loperamide is effective; in patients with ileostomy, loperamide treatment resulted in a 27% decrease in the wet weight of ostomy effluent (P < .02).16 Unlike loperamide, the opioid receptor agonist diphenoxylate crosses the blood-brain barrier.17 Nonetheless, diphenoxylate is limited in its abuse potential, because added atropine induces unpleasant anticholinergic effects when taken at high doses (eg, xerostomia, tachycardia, mydriasis).18,19 In small clinical studies, diphenoxylate and loperamide had similar efficacy for the treatment of chronic diarrhea, although some trials have shown a modest advantage for loperamide over diphenoxylate.20 Other antimotility agents include codeine, morphine, and opium tincture. These opioids are not restricted to the peripheral nervous system and so can generate CNS effects.21 Although patients often develop tolerance to the analgesic properties of opioids or opioid receptor agonists, tolerance to the antidiarrheal effect is rare, and the effective dose may remain constant for months to years.22
Recommendations for Use of Antimotility Agents Dosage of the selected first-line antimotility agent should be escalated in a stepwise manner at intervals of 3–5 days, until benefit is observed, adverse events occur, or the recommended
maximum dosage is reached (Table 1 and Figure 1). For diphenoxylate, some patients may benefit from doses that exceed the recommended maximum dosage. If the agent confers no benefit or induces adverse events, then administration should be suspended and treatment with a second-line agent initiated. If the patient experiences a partial response to the first-line agent, a second agent can be added and the dose escalated in the same stepwise fashion until the desired response is achieved. Patients may require multiple antimotility agents to attain maximal effect. Throughout the optimization process, patients should be provided with guidelines on dose titration because responses may vary with alterations in diet and/or changes in the course of the disease. Because of the gastrocolic reflex, antimotility agents should be administered 30–60 minutes preprandially.23 An additional dose provided immediately before sleep may help minimize trips to the bathroom at night.
Gastric Acid Hypersecretion Healthy individuals secrete an average of 750 mL/d (range, 100–1500 mL/d) of gastric fluid. Following intestinal resection, more than half of patients experience an increase in gastric acid release, which can reach up to 4100 mL/d.24 Gastric acid hypersecretion is usually transient and often resolves within a few weeks or months following resection.24,25 Although the mechanisms underlying this phenomenon have not been clearly defined, gastric acid hypersecretion may be caused by the loss of 1 or more endogenous intestinal inhibitors of gastric acid secretion.25 Prime candidates for the intestinal inhibitor include cholecystokinin, secretin, and neurotensin.26
Downloaded from pen.sagepub.com at TEMPLE UNIV on October 15, 2014
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Journal of Parenteral and Enteral Nutrition 38(Suppl 1)
Table 1. Medications Commonly Used to Treat Diarrhea in Patients With Short Bowel Syndrome. Etiology Rapid intestinal transit
Therapeutic Class Antimotility agent
Agent (OTC or Rx and Schedule, if Applicable) Loperamide (OTC)
Diphenoxylate (Rx, CV)
Gastric acid hypersecretion
Codeine (Rx, CII to CIV) Opium tincture (Rx, CII) Lansoprazole (OTC/Rx) Pantoprazole (Rx) Omeprazole (OTC/Rx) Esomeprazole (Rx) Rabeprazole (Rx) Dexlansoprazole (Rx) Famotidine (OTC) Ranitidine (OTC) Cimetidine (OTC) Clonidine (Rx)
Intestinal bacterial overgrowth Fat malabsorption
Proton pump inhibitor
Histamine receptor antagonist
α2-Adrenergic receptor agonist Somatostatin analogue Antibiotic
Pancreatic enzyme replacement
Octreotide (Rx) Metronidazole (Rx) Ciprofloxacin (Rx) Rifaximin (Rx) Augmentin (Rx) Doxycycline (Rx) Neomycin (Rx) Tetracycline (Rx) Pancrelipase (Rx)
Dosage 2–6 mg PO QID; maximum daily dose, 16 mg 2.5–7.5 mg PO QID; maximum daily dose, 20–25 mga 15–60 mg PO QID 0.3–1 mL PO QID 15–30 PO BID 20–40 mg PO/IV BID 20–40 mg PO BID 20–40 mg PO/IV BID 20 mg PO BID 30–60 mg PO BID 20–40 mg PO/IV BID 150–300 mg PO/IV BID 200–400 mg PO/IV QID 0.1–0.3 mg PO BID 0.1- to 0.3-mg patch Q7D 50–250 µg SC TID or QID 250 mg PO TID for 7–14 days 500 mg PO BID for 7–14 days 200–550 mg PO TID for 7–14 days 500 mg PO BID for 7–14 days 100 mg PO BID for 7–14 days 500 mg PO BID for 7–14 days 250–500 mg PO QID for 7–14 days 500 lipase units/kg per meal; maximum dose is 2500 lipase units/kg per meal or 10,000 lipase units/kg/d
BID, twice daily; CII–CV, drug schedule as established by the US Drug Enforcement Administration schedule of controlled drugs; IV, intravenous; OTC, over the counter; PO, by mouth; Q7D, every 7 days; QID, 4 times per day; Rx, available by prescription only; SC, subcutaneous; TID, 3 times per day. a Doses that exceed the maximum recommended dose may be required in some cases.
Gastric acid hypersecretion may have negative consequences for affected individuals, including aggravation of diarrhea, inactivation of pancreatic enzymes, and precipitation of peptic ulcer disease.23,25,27 Fortunately, patients have several pharmacologic options available. Proton pump inhibitors (PPIs), including lansoprazole, pantoprazole, omeprazole, and esomeprazole, are typical first-line agents of choice (Table 1 and Figure 1). PPIs irreversibly block the function of H+/K+ ATPase proton pumps, which normally secrete hydrogen ions into the gastric lumen.28 PPIs are highly effective. For example, omeprazole achieves near-complete suppression of gastric acid secretion among healthy adults.29 In patients with SBS, intravenous (IV) omeprazole 40 mg twice daily increased wet weight absorption by 0.78 kg/d (P < .05).30 Although generally well tolerated, PPIs are associated with small increases in the risks of community-acquired pneumonia over the short term and osteoporosis, bone fracture, and vitamin B12 deficiency over the long term.31,32 The risk of microscopic colitis is also
greater with PPI treatment.33 Furthermore, discontinuation may cause an increase in acid-related symptoms (rebound hypersecretion).34 Finally, because gastric acids normally act to reduce the concentration of ingested bacteria, acid suppressors may promote overgrowth of bacteria in the GI tract (see below).23 Typical second-line agents used to combat gastric hypersecretion include histamine type 2 receptor (H2) antagonists (eg, famotidine, ranitidine, cimetidine) and α2-adrenergic receptor agonists (eg, clonidine). H2 antagonists block the function of histamine, a local mediator of acid secretion released from the gastric mucosa in response to the hormone gastrin.35 In general, H2 antagonists are considered second-line treatment because of their decreased efficacy relative to PPIs.23,30 The effects of clonidine are not limited to inhibition of gastric acid hypersecretion. Clonidine stimulates α2-adrenergic receptors on enteric neurons that also reduce gastric and colonic motility and intestinal fluid secretion.36 Evidence
Downloaded from pen.sagepub.com at TEMPLE UNIV on October 15, 2014
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supporting clonidine use in patients with SBS is limited. In a study of 8 end-jejunostomy patients dependent on parenteral nutrition (PN), a 0.3-mg clonidine patch reduced fecal weight by 9% (P = .05) and decreased fecal sodium loss by 11% (P = .04).37 In addition, a case report describes 2 patients with SBS who were refractory to multiple antidiarrheal agents; treatment with clonidine reduced their ostomy output by approximately 2.5–3 L/d.38 Octreotide may be effective for patients who fail to respond sufficiently to other antidiarrheal therapies. Octreotide, a longacting analogue of the peptide hormone somatostatin, inhibits diarrhea through multiple mechanisms, including inhibition of gastrin and other GI hormones.39 Octreotide also inactivates adenylate cyclase and thereby inhibits movement of ions across the intestinal epithelium.39 In addition, octreotide prolongs intestinal transit time in patients with SBS.40 In a study of 10 end-jejunostomy patients dependent on PN support, octreotide reduced ostomy output by an average of 3.3 L/d (P < .03) and permitted reductions of PN volume of 1.3 L/d (P < .002).41 Use of octreotide is limited by its high cost, the inconvenience of administration by subcutaneous injection, and risk of associated adverse events, including cholelithiasis, which is already increased in patients with SBS.41,42 Furthermore, octreotide reduced intestinal adaptation following resection in some preclinical studies.43-46
Recommendations for Use of Acid Suppression Therapy Administration of acid suppression therapy should decrease stool output; if not, an increase in dosage or dosing frequency may be warranted.23 As with antimotility agents, acid suppressors should be initiated at a low dose and titrated upward to yield maximal efficacy with minimal adverse events. PPI treatment should be discontinued in the event of worsening diarrhea. If oral administration fails to achieve sufficient absorption, IV administration is an option for PPIs and H2 antagonists.30 H2 receptor antagonists may also be added to PN formulations. Patients should be closely monitored for acid rebound when PPIs or H2 antagonists are discontinued, and therapy should be restarted if necessary.31 Because clonidine was originally developed as an antihypertensive agent, hypotension is a concern when it is used for SBS.47 Therefore, slow escalation of clonidine dose along with regular blood pressure testing is recommended.38
Choleretic Diarrhea Because bile salts are absorbed primarily in the distal ileum, some patients with ileal resections
Pharmacologic Management of Diarrhea in Patients With Short Bowel Syndrome Vanessa J. Kumpf JPEN J Parenter Enteral Nutr 2014 38: 38S originally published online 24 January 2014 DOI: 10.1177/0148607113520618 The online version of this article can be found at: http://pen.sagepub.com/content/38/1_suppl/38S
Published by: http://www.sagepublications.com
On behalf of:
The American Society for Parenteral & Enteral Nutrition
Additional services and information for Journal of Parenteral and Enteral Nutrition can be found at: Email Alerts: http://pen.sagepub.com/cgi/alerts Subscriptions: http://pen.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Apr 22, 2014 OnlineFirst Version of Record - Jan 24, 2014 What is This?
Downloaded from pen.sagepub.com at TEMPLE UNIV on October 15, 2014
520618
research-article2014
PENXXX10.1177/0148607113520618Journal of Parenteral and Enteral NutritionKumpf
Invited Review
Pharmacologic Management of Diarrhea in Patients With Short Bowel Syndrome Vanessa J. Kumpf, PharmD, BCNSP1
Journal of Parenteral and Enteral Nutrition Volume 38 Supplement 1 May 2014 38S–44S © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0148607113520618 jpen.sagepub.com hosted at online.sagepub.com
Abstract Diarrhea associated with short bowel syndrome (SBS) can have multiple etiologies, including accelerated intestinal transit, gastric acid hypersecretion, intestinal bacterial overgrowth, and malabsorption of fats and bile salts. As a result, patients may need multiple medications to effectively control fecal output. The armamentarium of antidiarrheal drugs includes antimotility agents, antisecretory drugs, antibiotics and probiotics, bile acid–binding resins, and pancreatic enzymes. An antidiarrheal regimen must be individualized for each patient and should be developed using a methodical, stepwise approach. Treatment should be initiated with a single first-line medication at the low end of its dosing range. Dosage and/or dosing frequency can then be slowly escalated to achieve maximal effect while minimizing adverse events. If diarrhea remains poorly controlled, additional agents can be incorporated sequentially. If modification of the regimen is required, a single medication should be altered or exchanged at a time. After each adjustment of the regimen, sufficient time should be permitted to fully assess response (≥3–5 days) before initiating additional changes. SBS-associated malabsorption is a major obstacle to optimization of an antidiarrheal regimen because drug absorption is impaired. Patients may benefit from high dosages and/or frequent dosing intervals, liquid preparations, or nonoral routes of drug delivery. Although the diarrhea associated with SBS can be debilitating, effective pharmaceutical management has the potential to substantially improve health outcomes and quality of life for these patients. (JPEN J Parenter Enteral Nutr. 2014;38(suppl 1):38S-44S)
Keywords gastroenterology; research and diseases; adult; life cycle; probiotics; home nutrition support; nutrition; internal medicine
Management of short bowel syndrome (SBS) focuses on replacement of fluid and nutrient losses, achieving or maintaining adequate weight, and controlling diarrhea. Multiple factors contribute to diarrhea in patients with SBS, including accelerated intestinal transit, increased gastrointestinal (GI) secretions, bacterial overgrowth, and malabsorption of fats and bile salts. Diarrhea can negatively affect health outcomes for patients with SBS. For example, diarrhea leaves patients at increased risk of dehydration, micronutrient deficiencies, and weight loss. Furthermore, quality of life can be diminished by severe diarrhea associated with SBS. Patients have expressed fears related to eating because of probable increased stool output and reluctance to leave home because of possible fecal incontinence.1,2 In fact, patients with ostomies may face fewer disruptions to daily life than patients with colon-incontinuity because of reduced bathroom dependency.3 Both dietary manipulation and pharmacologic management of diarrhea have the potential to substantially improve overall health and quality of life for this patient population. This article focuses on pharmacologic management of diarrhea. Please refer to other resources for a discussion of diet manipulation for diarrhea reduction in patients with SBS.4-6
Antimotility Agents A primary cause of diarrhea in patients with SBS is increased intestinal motility, resulting in accelerated small bowel transit
time.7 The etiology underlying increased intestinal motility in SBS is unclear but has been assumed to be related to the loss of an inhibitor of intestinal motility normally released from the distal GI tract. Indeed, patients with end jejunostomy experience more rapid intestinal transit of liquids than patients with colon-in-continuity, perhaps because of lower plasma levels of peptide YY, glucagon-like peptide 1, and/or glucagon-like peptide 2.8-12 Accelerated intestinal motility is typically treated with opioids or opioid receptor agonists that inhibit contraction of intestinal smooth muscles. The resulting increase in intestinal From the 1Vanderbilt University Medical Center, Nashville, Tennessee. Financial disclosure: The publication of the supplement in which this article appears is supported by an educational grant from NPS Pharmaceuticals, Inc (Bedminster, NJ). Funding for medical writing assistance was provided by NPS Pharmaceuticals, Inc. V.J.K. has served as a consultant for NPS Pharmaceuticals, Inc. No financial compensation was provided to V.J.K. for the preparation of this work. Received for publication October 30, 2013; accepted for publication December 30, 2013. Corresponding Author: Vanessa J. Kumpf, PharmD, BCNSP, Vanderbilt University Medical Center, 1211 21st Ave S, 514 Medical Arts Bldg, Nashville, TN 37232, USA. Email: [email protected]
Downloaded from pen.sagepub.com at TEMPLE UNIV on October 15, 2014
Kumpf
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Figure 1. Treatment algorithm for the pharmacologic management of diarrhea associated with short bowel syndrome. H2 = histamine type-2 receptor.
transit time allows for greater nutrient absorption.13,14 Loperamide and diphenoxylate-atropine are typically the firstline choices for antimotility agents (Figure 1). As a peripherally restricted µ-opioid receptor agonist, loperamide does not engender undesirable central nervous system (CNS) effects, such as sedation, euphoric effects, or addiction.15 Furthermore, loperamide is effective; in patients with ileostomy, loperamide treatment resulted in a 27% decrease in the wet weight of ostomy effluent (P < .02).16 Unlike loperamide, the opioid receptor agonist diphenoxylate crosses the blood-brain barrier.17 Nonetheless, diphenoxylate is limited in its abuse potential, because added atropine induces unpleasant anticholinergic effects when taken at high doses (eg, xerostomia, tachycardia, mydriasis).18,19 In small clinical studies, diphenoxylate and loperamide had similar efficacy for the treatment of chronic diarrhea, although some trials have shown a modest advantage for loperamide over diphenoxylate.20 Other antimotility agents include codeine, morphine, and opium tincture. These opioids are not restricted to the peripheral nervous system and so can generate CNS effects.21 Although patients often develop tolerance to the analgesic properties of opioids or opioid receptor agonists, tolerance to the antidiarrheal effect is rare, and the effective dose may remain constant for months to years.22
Recommendations for Use of Antimotility Agents Dosage of the selected first-line antimotility agent should be escalated in a stepwise manner at intervals of 3–5 days, until benefit is observed, adverse events occur, or the recommended
maximum dosage is reached (Table 1 and Figure 1). For diphenoxylate, some patients may benefit from doses that exceed the recommended maximum dosage. If the agent confers no benefit or induces adverse events, then administration should be suspended and treatment with a second-line agent initiated. If the patient experiences a partial response to the first-line agent, a second agent can be added and the dose escalated in the same stepwise fashion until the desired response is achieved. Patients may require multiple antimotility agents to attain maximal effect. Throughout the optimization process, patients should be provided with guidelines on dose titration because responses may vary with alterations in diet and/or changes in the course of the disease. Because of the gastrocolic reflex, antimotility agents should be administered 30–60 minutes preprandially.23 An additional dose provided immediately before sleep may help minimize trips to the bathroom at night.
Gastric Acid Hypersecretion Healthy individuals secrete an average of 750 mL/d (range, 100–1500 mL/d) of gastric fluid. Following intestinal resection, more than half of patients experience an increase in gastric acid release, which can reach up to 4100 mL/d.24 Gastric acid hypersecretion is usually transient and often resolves within a few weeks or months following resection.24,25 Although the mechanisms underlying this phenomenon have not been clearly defined, gastric acid hypersecretion may be caused by the loss of 1 or more endogenous intestinal inhibitors of gastric acid secretion.25 Prime candidates for the intestinal inhibitor include cholecystokinin, secretin, and neurotensin.26
Downloaded from pen.sagepub.com at TEMPLE UNIV on October 15, 2014
40S
Journal of Parenteral and Enteral Nutrition 38(Suppl 1)
Table 1. Medications Commonly Used to Treat Diarrhea in Patients With Short Bowel Syndrome. Etiology Rapid intestinal transit
Therapeutic Class Antimotility agent
Agent (OTC or Rx and Schedule, if Applicable) Loperamide (OTC)
Diphenoxylate (Rx, CV)
Gastric acid hypersecretion
Codeine (Rx, CII to CIV) Opium tincture (Rx, CII) Lansoprazole (OTC/Rx) Pantoprazole (Rx) Omeprazole (OTC/Rx) Esomeprazole (Rx) Rabeprazole (Rx) Dexlansoprazole (Rx) Famotidine (OTC) Ranitidine (OTC) Cimetidine (OTC) Clonidine (Rx)
Intestinal bacterial overgrowth Fat malabsorption
Proton pump inhibitor
Histamine receptor antagonist
α2-Adrenergic receptor agonist Somatostatin analogue Antibiotic
Pancreatic enzyme replacement
Octreotide (Rx) Metronidazole (Rx) Ciprofloxacin (Rx) Rifaximin (Rx) Augmentin (Rx) Doxycycline (Rx) Neomycin (Rx) Tetracycline (Rx) Pancrelipase (Rx)
Dosage 2–6 mg PO QID; maximum daily dose, 16 mg 2.5–7.5 mg PO QID; maximum daily dose, 20–25 mga 15–60 mg PO QID 0.3–1 mL PO QID 15–30 PO BID 20–40 mg PO/IV BID 20–40 mg PO BID 20–40 mg PO/IV BID 20 mg PO BID 30–60 mg PO BID 20–40 mg PO/IV BID 150–300 mg PO/IV BID 200–400 mg PO/IV QID 0.1–0.3 mg PO BID 0.1- to 0.3-mg patch Q7D 50–250 µg SC TID or QID 250 mg PO TID for 7–14 days 500 mg PO BID for 7–14 days 200–550 mg PO TID for 7–14 days 500 mg PO BID for 7–14 days 100 mg PO BID for 7–14 days 500 mg PO BID for 7–14 days 250–500 mg PO QID for 7–14 days 500 lipase units/kg per meal; maximum dose is 2500 lipase units/kg per meal or 10,000 lipase units/kg/d
BID, twice daily; CII–CV, drug schedule as established by the US Drug Enforcement Administration schedule of controlled drugs; IV, intravenous; OTC, over the counter; PO, by mouth; Q7D, every 7 days; QID, 4 times per day; Rx, available by prescription only; SC, subcutaneous; TID, 3 times per day. a Doses that exceed the maximum recommended dose may be required in some cases.
Gastric acid hypersecretion may have negative consequences for affected individuals, including aggravation of diarrhea, inactivation of pancreatic enzymes, and precipitation of peptic ulcer disease.23,25,27 Fortunately, patients have several pharmacologic options available. Proton pump inhibitors (PPIs), including lansoprazole, pantoprazole, omeprazole, and esomeprazole, are typical first-line agents of choice (Table 1 and Figure 1). PPIs irreversibly block the function of H+/K+ ATPase proton pumps, which normally secrete hydrogen ions into the gastric lumen.28 PPIs are highly effective. For example, omeprazole achieves near-complete suppression of gastric acid secretion among healthy adults.29 In patients with SBS, intravenous (IV) omeprazole 40 mg twice daily increased wet weight absorption by 0.78 kg/d (P < .05).30 Although generally well tolerated, PPIs are associated with small increases in the risks of community-acquired pneumonia over the short term and osteoporosis, bone fracture, and vitamin B12 deficiency over the long term.31,32 The risk of microscopic colitis is also
greater with PPI treatment.33 Furthermore, discontinuation may cause an increase in acid-related symptoms (rebound hypersecretion).34 Finally, because gastric acids normally act to reduce the concentration of ingested bacteria, acid suppressors may promote overgrowth of bacteria in the GI tract (see below).23 Typical second-line agents used to combat gastric hypersecretion include histamine type 2 receptor (H2) antagonists (eg, famotidine, ranitidine, cimetidine) and α2-adrenergic receptor agonists (eg, clonidine). H2 antagonists block the function of histamine, a local mediator of acid secretion released from the gastric mucosa in response to the hormone gastrin.35 In general, H2 antagonists are considered second-line treatment because of their decreased efficacy relative to PPIs.23,30 The effects of clonidine are not limited to inhibition of gastric acid hypersecretion. Clonidine stimulates α2-adrenergic receptors on enteric neurons that also reduce gastric and colonic motility and intestinal fluid secretion.36 Evidence
Downloaded from pen.sagepub.com at TEMPLE UNIV on October 15, 2014
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supporting clonidine use in patients with SBS is limited. In a study of 8 end-jejunostomy patients dependent on parenteral nutrition (PN), a 0.3-mg clonidine patch reduced fecal weight by 9% (P = .05) and decreased fecal sodium loss by 11% (P = .04).37 In addition, a case report describes 2 patients with SBS who were refractory to multiple antidiarrheal agents; treatment with clonidine reduced their ostomy output by approximately 2.5–3 L/d.38 Octreotide may be effective for patients who fail to respond sufficiently to other antidiarrheal therapies. Octreotide, a longacting analogue of the peptide hormone somatostatin, inhibits diarrhea through multiple mechanisms, including inhibition of gastrin and other GI hormones.39 Octreotide also inactivates adenylate cyclase and thereby inhibits movement of ions across the intestinal epithelium.39 In addition, octreotide prolongs intestinal transit time in patients with SBS.40 In a study of 10 end-jejunostomy patients dependent on PN support, octreotide reduced ostomy output by an average of 3.3 L/d (P < .03) and permitted reductions of PN volume of 1.3 L/d (P < .002).41 Use of octreotide is limited by its high cost, the inconvenience of administration by subcutaneous injection, and risk of associated adverse events, including cholelithiasis, which is already increased in patients with SBS.41,42 Furthermore, octreotide reduced intestinal adaptation following resection in some preclinical studies.43-46
Recommendations for Use of Acid Suppression Therapy Administration of acid suppression therapy should decrease stool output; if not, an increase in dosage or dosing frequency may be warranted.23 As with antimotility agents, acid suppressors should be initiated at a low dose and titrated upward to yield maximal efficacy with minimal adverse events. PPI treatment should be discontinued in the event of worsening diarrhea. If oral administration fails to achieve sufficient absorption, IV administration is an option for PPIs and H2 antagonists.30 H2 receptor antagonists may also be added to PN formulations. Patients should be closely monitored for acid rebound when PPIs or H2 antagonists are discontinued, and therapy should be restarted if necessary.31 Because clonidine was originally developed as an antihypertensive agent, hypotension is a concern when it is used for SBS.47 Therefore, slow escalation of clonidine dose along with regular blood pressure testing is recommended.38
Choleretic Diarrhea Because bile salts are absorbed primarily in the distal ileum, some patients with ileal resections
