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Gastrointestinal Disorders Table 23. Recommended Treatment Regimens for Chronic HCV Infection in Treatment-Naive Patients With or Without Compensated Cirrhosis by HCV Genotypea Genotype 1a 1b 2 3 4 5 or 6 Without Cirrhosis GLE (300 mg)/PIB (120 mg) for 8 wk LDV (90 mg)/ b SOF (400 mg) for 12 wk...

Gastrointestinal Disorders Table 23. Recommended Treatment Regimens for Chronic HCV Infection in Treatment-Naive Patients With or Without Compensated Cirrhosis by HCV Genotypea Genotype 1a 1b 2 3 4 5 or 6 Without Cirrhosis GLE (300 mg)/PIB (120 mg) for 8 wk LDV (90 mg)/ b SOF (400 mg) for 12 wk VEL (100 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wk VEL (100 mg)/SOF (400 mg) for 12 wk EBR (50 mg)/GZR (100 mg) for 12 wkc b LDV (90 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wk VEL (100 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wk VEL (100 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wk VEL (100 mg)/SOF (400 mg) for 12 wk EBR (50 mg)/GZR (100 mg) for 12 wk LDV (90 mg)/SOF (400 mg) for 12 wke GLE (300 mg)/PIB (120 mg) for 8 wk VEL (100 mg)/SOF (400 mg) for 12 wk LDV (90 mg)/SOF (400 mg) for 12 wkg With Compensated Cirrhosis GLE (300 mg)/PIB (120 mg) for 8 wk LDV (90 mg)/SOF (400 mg) for 12 wk VEL (100 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wk VEL (100 mg)/SOF (400 mg) for 12 wk EBR (50 mg)/GZR (100 mg) for 12 wk LDV (90 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wk VEL (100 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wk d VEL (100 mg)/SOF (400 mg) for 12 wk GLE (300 mg)/PIB (120 mg) for 8 wkf VEL (100 mg)/SOF (400 mg) for 12 wk EBR (50 mg)/GZR (100 mg) for 12 wk LDV (90 mg)/SOF (400 mg) for 12 wk (Same recommendations for genotype 5 or 6 with or without compensated cirrhosis) See guidelines for treatment recommendations after failure of Pegylated interferon therapy or direct-acting antivirals. For patients who are uninfected with HIV, and whose HCV RNA less than 6 million IU/mL, can use 8 week duration of therapy. c Consider 8-week regimen if mild fibrosis. d Only recommended in patients without baseline NS5A Resistance Associated Substitutions (RAS) Y93H. e Consider 8-week regimen if no cirrhosis, HCV RNA less than 6 million IU/mL, and absence of genotype 4r. f For patients co-infected with HIV, 12-week duration is recommended. a b Not recommended for genotype 6e if subtype is known. EBR = elbasvir; GLE = glecaprevir; GZR = grazoprevir; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LDV = ledipasvir; PIB = pibrentasvir; SOF = sofosbuvir; VEL = velpatasvir. See treatment guidelines for alternative recommendations. g 5. Monitoring a. Baseline HCV RNA, genotype, quantitative HCV RNA (HCV viral load), CBC, liver function tests (LFTs), and calculated GFR. HIV and hepatitis B surface antigen testing. Pregnancy test for women. Evaluate for potential drug-drug interactions. b. On therapy: Medication adherence, potential drug-drug interactions. c. After treatment: Check HCV RNA at 12 weeks to assess for SVR. 6. Prevention of HCV a. No vaccine or immune globulin available b. Risk factor modification i. Intravenous drug abuse: Methadone maintenance, syringe exchange ii. Sexual contact: Appropriate barrier contraception iii. Avoid blood exposure: Occupational (universal precautions) or other contact (e.g., sharing toothbrushes or razors or receiving a tattoo) iv. The HAV and HBV vaccine to prevent further progression of liver disease ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-165 Gastrointestinal Disorders ii. Chemoreceptor trigger zone (located in the area postrema): Mediated by dopamine (D2), serotonin, and some histamine (H1) and muscarinic (M1) and substance P/neurokinin 1; major stimuli include: (a) Medications: Opiates, dopamine agonists, digoxin, chemotherapeutic agents, macrolides, general anesthetics (b) Metabolic disturbances (uremia, diabetic ketoacidosis, hypercalcemia, hypoxemia) (c) Bacterial toxins (d) Radiation therapy iii. Vestibular labyrinths: Mediated through H1 and M1. Major stimuli include: (a) Motion sickness (b) Labyrinth infection iv. Cerebral cortex: Receptor involvement not well characterized; noxious odors, visions, and tastes Table 24. Common Clinical Conditions Associated with Nausea and Vomiting Category Infectious Gastrointestinal Central nervous system Endocrine or metabolic Cardiovascular Other Conditions Viral or bacterial gastritis or gastroenteritis, pyelonephritis Pancreatitis, gastroparesis, hepatitis, gastroesophageal reflux disease Migraine, stroke, pain, seizures, motion sickness, meningitis Pregnancy, uremia, diabetic ketoacidosis, hypercalcemia Myocardial infarction, heart failure Postoperative, cerebral mass b. Clinical consequences of nausea and vomiting include dehydration, electrolyte disturbances, aspiration, and Mallory-Weiss syndrome. B. Treatment and prevention strategies 1. Remove or treat the underlying cause (Table 24) 2. Correct dehydration and electrolyte disturbances. Oral rehydration is preferred, if possible, with oral rehydration solutions (e.g., Pedialyte, diluted Gatorade). 3. Drug treatment: Use drugs that target receptors involved with stimuli. May need combination of drugs with different mechanisms. Also may need alternative dose forms (intravenous, subcutaneous, suppository). a. Major drug classes of antiemetics: All are antagonists at the respective receptors. (Table 25) b. Drugs of choice for different situations include: i. General medical use: phenothiazines, serotonin antagonists ii. Chemotherapy induced: serotonin antagonists, NK1 antagonists, corticosteroids, and olanzapine as adjunctive therapy (See “Oncology Supportive Care” chapter for treatment and prevention.) iii. Postoperative: serotonin antagonists, scopolamine, corticosteroids iv. Motion sickness: antihistamines, scopolamine v. Pregnancy: phosphorylated carbohydrate solution, pyridoxine, antihistamines, ginger vi. Gastroparesis: metoclopramide ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-167 Gastrointestinal Disorders Table 25. Select Antiemetics Drug Formulations Comments Promethazine (Phenergan) Tablet, suppository, injection Antidopaminergic, anticholinergic, and antihistaminergic activity; can cause EPS, injection-site irritation (do not use subcutaneously), sedation IV formulation should be diluted (risk of tissue necrosis) Prochlorperazine (Compazine) Tablet, syrup, suppository, injection Mainly antidopaminergic activity; can cause EPS, injection-site irritation (do not use subcutaneously) Ondansetron (Zofran) Tablet, ODT, oral solution, injection, oralsoluble film (Zuplenz) Overall, well tolerated; no liquid required for ODT or soluble film; contraindicated with apomorphine; associated with QTc prolongation; correct hypomagnesemia and hypokalemia Granisetron (Kytril, Sancuso, Sustol) Injection, tablet, oral solution, patch Overall, well tolerated; associated with QTc prolongation Palonosetron (Aloxi) Injection Long duration of action is 24 hr to 5 days; only one dose required Tablet, oral liquid, injection Take 30–60 min before travel; risk of sedation and anticholinergic adverse effects Injection, tablet Risk of extrapyramidal adverse effects; risk of QTc prolongation; requirement for baseline ECG and 2- to 3-hr postdose cardiac monitoring with the use of injectable agents Injecton, tablet, oral solution Short-term use to prevent postoperative nausea and vomiting or chemotherapy-induced nausea and vomiting Aprepitant, fosaprepitant (Emend) Capsule, injection Targets substance P/neurokinin 1 (NK1) receptors; reduces efficacy of warfarin and oral contraceptives; dose-dependent inhibitor of CYP3A4 Netupitant / palonosetron (Akynzeo) Capsule Targets substance P/neurokinin 1 (NK1) receptors and 5-HT3; avoid in severe renal or hepatic disease, drug-drug interactions by CYP enzymes Rolapitant (Varubi) Tablet Targets neurokinin 1 (NK1) receptors; long half-life (7 days) Scopolamine (Transderm Scop) Patch Apply topically (often behind the ear) 4 hr before travel; can wear for up to 72 hr; do not cut patch; risk of anticholinergic adverse effects Dronabinol (Marinol), nabilone (Cesamet) Capsule Delta-9 tetrahydrocannabinol; targets central endogenous cannabinoid receptors; used most often for chemotherapy-induced N/V; can cause appetite stimulation, euphoria, cognitive impairment Phosphorylated carbohydrate solution (Emetrol) Oral solution Use undiluted for best effect; do not use >1 hr (or maximum of five doses); safe in pregnancy; avoid in diabetes and fructose intolerance Doxylamine/ pyridoxine (Diclegis, Bonjesta) Delayed-release tablet (10 mg/10 mg) Prescription product approved for NVP in women who do not respond to conservative management; OTC doxylamine and pyridoxine may be considered; pregnancy category A Phenothiazines Serotonin antagonists Antihistamines Dimenhydrinate (Dramamine), cyclizine (Marezine), meclizine (Bonine), doxylamine (Unisom) Butyrophenones Haloperidol, droperidol Corticosteroids Dexamethasone (Decadron) Neurokinin 1 antagonists Miscellaneous agents CYP = cytochrome P450; ECG = electrocardiogram; EPS = extrapyramidal symptoms; N/V = nausea and vomiting; NVP = nausea and vomiting of pregnancy; ODT = orally disintegrating tablet; SR = sustained release. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-168 Gastrointestinal Disorders c. Nondrug therapy for nausea and vomiting: acupressure and acustimulation wristbands (Sea-Band, Reliefband); work by stimulating the pericardium 6 (P6) point. VIII. PANCREATITIS A. Classification and pathophysiology 1. Acute a. Characterized by inflammation in the pancreas ranging from mild to severe b. An initial insult leads to the release of trypsin in the pancreas, leading to the activation of pancreatic enzymes and intrapancreatic inflammation and complications. It can then progress to extrapancreatic complications. It is usually reversible once the underlying cause is addressed. c. Two distinct phases i. Early (within 1 week): associated with systemic inflammatory response syndrome or organ damage ii. Late (more than 1 week): associated with local complications d. Typical signs and symptoms include abdominal pain and distension, nausea, vomiting, jaundice, and fever. i. Local complication: necrosis, hemorrhage, pseudocyst, abscess, infection ii. Systemic complications: systemic inflammatory response syndrome, acute respiratory distress syndrome, shock, organ failure e. Main causes of acute pancreatitis i. Long-term alcohol abuse ii. Gallstones iii. Drugs (Box 5) Box 5. Common Causes of Drug-Induced Pancreatitis Amiodarone Asparaginase Azathioprine/mercaptopurine Cannabis Didanosine Diuretics (furosemide, hydrochlorothiazide) Estrogens Exenatide Mesalamine/sulfasalazine Pentamidine Sitagliptin Tetracycline Trimethoprim/sulfamethoxazole Valproic acid iv. Post–endoscopic retrograde cholangiopancreatography v. Hypertriglyceridemia (generally greater than 1000 mg/dL) vi. Idiopathic vii. Structural abnormalities viii. Toxins (scorpion venom) ix. Trauma x. Ischemia ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-169 Gastrointestinal Disorders 2. Chronic a. Characterized by irreversible structural and functional loss of pancreatic function caused by long-standing inflammation and repeated injury b. Repeated injury results in loss of both exocrine and endocrine function. c. Typical signs and symptoms include chronic abdominal pain, steatorrhea, weight loss or cachexia, jaundice, and hyperglycemia. Complications include diabetes, pseudocysts, calcification, ascites, and biliary stricture. d. Risk factors for chronic pancreatitis are based on the M-ANNHEIM classification. The M-ANNHEIM classification system is an objective, relatively noninvasive approach to categorizing patients with acute or chronic pancreatitis on the basis of their disease etiology, clinical stage, and disease severity. M = Multiple risk factors A = Alcohol consumption N = Nicotine N = Nutritional factors (high fat and protein, hyperlipidemia) H = Hereditary factors E = Efferent duct factors I = Immunologic factors M = Miscellaneous and rare factors (includes drugs) B. Diagnosis 1. Acute pancreatitis a. Diagnosis is typically based on two of the three following criteria: i. Presence of abdominal pain ii. Laboratory diagnosis: Serum lipase (greater than 3 times the ULN) is the most sensitive test. Patients may also have hyperglycemia and other electrolyte abnormalities related to vomiting. Patients often have a leukocytosis and a fever. iii. Imaging: Abdominal ultrasonography and computed tomography (CT) scan to evaluate pancreas, biliary system, and presence of local complications b. Severity and prognosis (Table 26) Table 26. Common Scoring Systems to Classify Severity and Prognosis of Acute Pancreatitis Atlanta Symposium Criteria for Acute Pancreatitis Mild: absence of organ failure or local complications Moderately severe: local complications or transient organ failure (< 48 hr) Severe: persistent organ failure > 48 hr Ranson Criteria for Prognosisa At admission: Within next 48 hr: Age > 55 yr (>70 yr) Decrease in hematocrit by > 10% (same) WBC >16,000/L (18,000/L) Estimated fluid sequestration Blood glucose > 200 mg/dL of > 6 L (4 L) (220 mg/dL) Serum calcium < 8 mg/dL (same) Serum lactate dehydrogenase > 350 IU/L (>400 IU/L) Pao2 < 60 mm Hg (omitted) Serum AST > 250 IU/L (same) BUN concentration increase > 5 mg/dL after IV fluid hydration (> 2 mg/dL) Base deficit of > 4 mmol/L (6 mmol/L) Values in parentheses are for gallstone induced; meeting more than three criteria indicates severe disease. AST = aspartate transaminase; BUN = blood urea nitrogen; WBC = white blood cell count. a ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-170 Gastrointestinal Disorders 2. Chronic pancreatitis: Diagnosis is typically based on the clinical signs and symptoms plus laboratory and imaging. a. Laboratory diagnosis: Serum lipase may be normal; hyperglycemia and low albumin or prealbumin may also be present. b. Imaging: CT scan may reveal pancreatic calcification or pseudocyst. C. Treatment strategies 1. Acute pancreatitis: Treatment is largely supportive; should include removal or treatment of underlying cause if possible. a. Temporarily withhold oral intake and provide rehydration with intravenous fluids, typically 250–500 mL/hour of lactated Ringer or normal saline solution. American Gastroenterological Association offers a recommendation for goal-directed intravenous fluids titrated to maintain heart rate; mean arterial pressure; central venous pressure; urine output; blood, urea, and nitrogen concentration; and hematocrit (Conditional recommendation / very low quality evidence). Treat electrolyte disturbances (hypokalemia, hypocalcemia, hyperglycemia). b. Pain management involves the use of intravenous narcotics (avoid meperidine). Patient-controlled analgesia is often used. c. Antiemetics: Intravenous ondansetron, prochlorperazine, or promethazine d. Nutrition: If pancreatitis is mild, then early (less than 24 hours) oral feeding can be resumed if no vomiting is present. If severe pancreatitis is present, use enteral nutrition to prevent infectious complications. Avoid total parenteral nutrition (higher rates of infection, mortality, and length of stay). e. Antibiotics, in general, are not recommended for routine prophylaxis in severe pancreatitis. Antibiotics can be used if extrapancreatic infection is present. If infected necrosis is present, then carbapenems, fluoroquinolones, or metronidazole may be useful in delaying the need for intervention. f. Endoscopic retrograde cholangiopancreatography may be needed for cholangitis or gallstone pancreatitis. This is often followed by cholecystectomy to prevent future episodes. 2. Chronic pancreatitis: Treatment is largely symptomatic. a. Abstinence from alcohol is essential. Pharmacologic intervention and supportive care (e.g., Alcoholics Anonymous) may be needed. Smoking cessation is also recommended by the ACG guidelines (strong recommendation, very low-quality evidence). b. Antioxidant therapy can be considered to treat pain with chronic pancreatitis. The antioxidants used in clinical trials vary in type and dosage but commonly include selenium, ascorbic acid, beta-carotene, and methionine (conditional recommendation, moderate-quality of evidence). c. Pain management often requires a combination of nonnarcotic and narcotic analgesics (long-acting morphine, oxycodone, or transdermal fentanyl) in combination with pancreatic enzyme replacement. Avoid acetaminophen if long-term alcohol use is a factor. Consider adjunctive medications such as pregabalin or selective serotonin reuptake inhibitors (SSRIs) in patients who tolerate oral medications to minimize opioid needs. d. Antiemetics: Oral ondansetron, prochlorperazine, or promethazine as needed e. Nutrition: Goal is to maximize caloric intake and weight gain and reduce steatorrhea. May need more frequent, lower-fat meals and fat-soluble vitamin supplementation. Long-term enteral or parenteral nutrition may be required. 3. Pancreatic enzyme replacement therapy a. Simulate the digestion of food that normally occurs with normal pancreatic enzyme release to reduce maldigestion and malabsorption. Pancreatic enzyme replacement therapy is recommended if the patient experiences weight loss, malnutrition, diarrhea, steatorrhea, osteoporosis, or osteopenia (conditional recommendation, low level of evidence). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-171 Gastrointestinal Disorders b. Products are enteric-coated microspheres or microtablets that contain lipase, amylase, and protease. Meant to mix with food, they release enzymes at intestinal pH values greater than 5.5. Products should not be crushed or chewed. c. Enzyme products were historically considered nutritional supplements. The FDA has now mandated FDA approval of all enzyme products. (Table 27) Table 27. Selected Pancreatic Enzyme Replacement Products Brand Name Viokace Creon Zenpep Pancreaze Pertzye d. Lipase (units) 10,440 Amylase (units) 39,150 Protease (units) 39,150 20,880 78,300 78,300 3000 15,000 9500 6000 30,000 19,000 12,000 60,000 38,000 24,000 120,000 76,000 36,000 3000 180,000 14,000 114,000 10,000 5000 24,000 17,000 10,000 42,000 32,000 15,000 63,000 47,000 20,000 84,000 63,000 25,000 105,000 79,000 40,000 2600 168,000 15,200 126,000 8800 4200 24,600 14,200 10,500 61,500 35,500 16,800 98,400 56,800 21,000 83,900 54,700 37,000 4000 149,900 15,125 97,300 14,375 8000 30,250 28,750 16,000 60,500 57,500 24,000 90,750 86,250 Formulation Immediate-release tablet; must be administered in combination with a proton pump inhibitor Capsules with enteric-coated microspheres (0.17–1.6 mm) Capsules with enteric-coated beads (1.8–1.9 mm for 3000/5000 units; 2.2–2.5 mm for all other strengths) Capsules with enteric-coated microtablets (2 mm) Capsules with bicarbonate-buffered enteric-coated microspheres (0.8–2 mm) Dosing is based on the lipase content (units) of the product. i. Starting adult doses are generally 40,000–50,000 units per meal, with a half dose for snacks. May also use weight-based dosing of 500–1000 units/kg per meal for those older than 4 years. ii. Maximum dose is 2500 units/kg per dose, 10,000 units/kg/day, or 90,000 units per meal. iii. Give enzymes with meals as opposed to before or after meals. iv. Titrate according to weight gain and reduction in steatorrhea. v. May need to add PPI if maximal response is not seen. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-172 Gastrointestinal Disorders e. Adverse effects of pancreatic enzyme therapy i. Nausea or abdominal cramping ii. Enzymes are derived from porcine pancreas; this is contraindicated if a pork allergy is present. iii. Hyperuricosuria, hyperuricemia iv. Fibrosing colonopathy (generally seen with doses greater than 10,000 units/kg/day) v. Pregnancy category C IX. DIARRHEA A. Classification and pathophysiology 1. Clinical definition: Alteration in a normal bowel movement characterized by an increase in the water content, volume, or frequency (more than three per day) of stool a. Acute is generally considered less than 72 hours to 14 days. b. Chronic is generally considered more than 14–30 days. 2. Can be classified into several major categories related to underlying cause a. Secretory i. Secondary to enhanced secretion by intestinal mucosa; often, large, watery volume with loss of electrolytes ii. Common causes: Bacterial or viral or bacterial enteritis, gastric hypersecretion, carcinoid, stimulant laxatives, bile acid malabsorption, celiac disease, IBD (mucosal) b. Osmotic i. Secondary to a hyperosmolar gradient in the intestinal lumen ii. Common causes: Osmotic laxatives, carbohydrate malabsorption (lactase deficiency), fat malabsorption (pancreatic insufficiency), short bowel syndrome c. Exudative or inflammatory i. Secondary to inflammation or infiltration or invasion of the intestinal mucosa ii. Common causes: IBD, invasive infection (C. difficile toxin, enterotoxigenic Escherichia coli, cytomegalovirus, Shigella species), ischemic colitis, radiation enterocolitis, neoplasm d. Altered motility or motor function i. Secondary to autonomic nerve dysfunction ii. Common causes: diabetic neuropathy, postvagotomy, hyperthyroidism, IBS, Addison disease 3. Drug-induced diarrhea can occur by a variety of mechanisms. See Box 6 for a list of medications that commonly cause diarrhea. Box 6. Common Causes of Drug-Induced Diarrhea Acarbose or miglitol Antibiotics Antineoplastics Colchicine Digoxin Laxatives Levothyroxine (over-replacement) Metoclopramide NSAIDs Prostaglandins (misoprostol) Orlistat Sorbitol (sugar-free products) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-173 Gastrointestinal Disorders B. Diagnosis 1. Conduct a thorough patient history. a. Evaluate for disease- and drug-induced causes (laxative, recent antibiotic use), recent travel history, and temporal relation to food intake. b. Assess fluid and electrolyte status. c. Assess CBC and stool culture, and evaluate for ova and parasites if infectious cause is suspected. Assess for C. difficile toxin and culture if there has been recent antibiotic use or hospitalization. d. Evaluate stool pH, electrolytes, osmolarity, or fat content, if indicated. e. Imaging (abdominal CT scan) or endoscopy with biopsy may be indicated, particularly for inflammatory diarrhea or suggestion of neoplasm or celiac disease. 2. Referral to higher level of care or further evaluation may be necessary for some patients. a. Immunocompromised b. Infants and children c. Pregnant women d. Presence of fever e. Blood in the stool f. Weight loss (greater than 5%) g. Suspected invasive infection C. Treatment strategies 1. Removal or treatment of underlying causes, if possible 2. Rehydration a. Intravenous fluids appropriate for hospitalized patients b. Oral rehydration appropriate for all patients if no vomiting is present i. Sodium and glucose are key ingredients of oral rehydration solutions, because they have active uptake into the intestinal mucosa even during active diarrhea. This results in water being pulled back into circulation. Other formulations (popsicles) are also available. ii. Gatorade may need to be diluted because it has a large amount of carbohydrates. 3. Dietary modifications a. Avoid dairy products because transient lactase deficiency can occur. b. “BRAT” diet for adults (mild foods such as bananas, rice, applesauce, toast) is sometimes recommended for short-term use, though definitive supporting data are limited. c. May need to interrupt feedings for pediatric patients 4. Drug therapy for diarrhea is listed in Table 28 (see “Infectious Diseases” chapter for management of infectious causes) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-174 Gastrointestinal Disorders Table 28. Select Therapies for the Management of Diarrhea Drugs Bismuth subsalicylate Mechanism Antisecretory, binds toxins Role Mild-moderate diarrhea; prevention of traveler’s diarrhea Crofelemer (Mytesi) Lactase Gastrointestinal chloride channel inhibitor Enzyme Loperamide μ-Receptor agonist Octreotide Antisecretory suppression of hormone release Opiates, tincture of opium, diphenoxylate plus atropine μ-Receptor agonist Antiretroviral therapyassociated diarrhea in patients with HIV Lactase deficiency or intolerance Mild to moderate noninvasive diarrhea; adjunctive to other nonopiate therapies Treatment of tumorassociated diarrhea (VIPoma [VernerMorrison syndrome], carcinoid); HIV-associated diarrhea Moderate to severe noninvasive diarrhea; suboptimal response to loperamide or bismuth; refractory diarrhea Prevention of antibioticassociated diarrhea; adjunctive therapy for treatment of C. difficile; small intestinal bacterial overgrowth Probiotics Competition (Lactobacillus, with pathogenic Saccharomyces spp.) organisms, production of antimicrobial substances, enhancement of immune response Teduglutide (Gattex) GLP-2 analog Approved for adult patients with short bowel syndrome who are dependent on parenteral support Adverse Effects and Precautions Stool discoloration; avoid in salicylate allergy, age <12 yr, pregnancy, nursing; caution with anticoagulants; can bind other drugs; can interfere with some radiographic procedures Upper respiratory infection, bronchitis, cough, bilirubin elevation Well tolerated Minimal CNS effects; avoid if suspected invasive infection; pregnancy category B Hyperglycemia, gallstone formation CNS effects, respiratory depression; constipation, possible anticholinergic effects with atropine; avoid if suspected invasive infection Well tolerated; caution if severely immunocompromised Colonic neoplasms (colonoscopy recommended every 5 yr); intestinal obstruction; biliary/ pancreatic disease (bilirubin, amylase, lipase, alkaline phosphatase, every 6 mo) CNS = central nervous system; GLP-2 = glucagon-like peptide-2. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-175 Gastrointestinal Disorders X. CONSTIPATION A. Definition and pathophysiology 1. Bowel symptoms (e.g., difficult or infrequent passage of stool, hardness of stool, or a feeling of incomplete evacuation) may occur in isolation or secondary to another underlying disorder. The 2013 guidelines distinguish between normal-transit constipation and slow-transit constipation. Another definition is “a symptom based disorder defined as unsatisfactory defecation and is characterized by infrequent stools, difficult stool passage, or both.” (Am J Gastroenterol 2014;109:S2-26) 2. May also be characterized by difficulty with or incomplete evacuation, straining, or presence of hard, dry stools. Abdominal pain and distension can occur, as well as low back pain and anorexia. 3. Pathophysiology is related to many different factors. Common causes include: a. Altered motility (e.g., ileus) b. Neurogenic causes (autonomic neuropathies, Parkinson disease) c. Endocrine or metabolic disorders (e.g., hypothyroidism, diabetes, hypokalemia, hypercalcemia, uremia) d. Pregnancy e. Psychogenic causes f. Structural abnormalities or obstruction g. Nutritional (e.g., reduced fiber and water intake) h. Medications (Box 7) 4. Constipation that is not caused by an underlying organic cause is called chronic idiopathic constipation (CIC) or functional constipation. Box 7. Common Causes of Drug-Induced Constipation Aluminum-containing drugs (antacids, sucralfate) Antihistamines Benzodiazepines Bile acid sequestrants Calcium channel blockers Calcium supplements and antacids Diuretics Iron supplements Opioids Phenothiazines Scopolamine, benztropine Tricyclic antidepressants ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-176 Gastrointestinal Disorders B. Diagnosis 1. Evaluate patient history thoroughly. a. Establish patient baseline and evaluate for disease- and drug-induced causes. b. Assess fluid and electrolyte status, thyroid function c. Imaging (abdominal CT scan or radiograph) may be necessary to assess for ileus, obstruction, or dilatation. 2. Referral for further evaluation may be necessary for some patient populations. a. Symptoms for more than 1–2 weeks despite treatment b. Considerable pain or cramping c. Pregnancy d. Presence of fever e. Blood in the stool f. Reduction in stool caliber g. Weight loss h. Paraplegia, quadriplegia 3. Diagnosis of CIC (functional constipation) is based on the Rome IV criteria, which is presence of two or more of the following over the previous 3 months: a. Straining during at least 25% of defecations b. Lumpy or hard stools in at least 25% of defecations c. Sensation of incomplete evacuation for at least 25% of defecations d. Sensation of anorectal obstruction or blockage for at least 25% of defecations e. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) f. Fewer than three defecations per week C. Treatment strategies 1. Remove or treat underlying causes, if possible. 2. Nonpharmacologic interventions a. Increase fluid intake to 6–8 glasses of water per day, although minimal evidence to support efficacy if dehydration is not present. b. Increase dietary fiber to 20–30 g/day. c. Incorporate or increase exercise to 3–5 days/week. d. Modifying behaviors: Toilet training and toileting position 3. Drug therapy for prevention and treatment of constipation (Table 29) a. Choose drug therapy on the basis of desired onset of action, patient preference, presence of potential contraindications, and use in special populations. b. Provide patient education on alternative dose forms (enema, suppository). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-177 Gastrointestinal Disorders Table 29. Drug Therapy Options for Treatment and Prevention of Constipation Drugs Role Saline osmotic laxatives Magnesium Acute or intermittent constipation, citrate, magnesium preoperative or preprocedure bowel hydroxide, sodium preparation phosphate Osmotic laxatives Glycerin Lactulose Polyethylene glycol Lactitol (Pizensy) Stimulant laxatives Bisacodyl Senna Comments Fast onset (15 min to 3 hr); avoid in renal impairment, HF, cirrhosis; FDA warning regarding oral sodium phosphate and development of acute phosphate nephropathy (avoid use for bowel preparations) Management of acute or intermittent constipation; used in pediatric patients Management of acute, intermittent, or chronic constipation, including CIC; useful in concomitant in chronic liver disease Acute or chronic constipation; effective for CIC; preoperative/ colon preparation Management of CIC in adults Suppository; fast onset (within 1 hr) Short-term relief of acute or intermittent constipation or as part of preoperative or colonoscopy bowel preparation Short-term relief of acute or intermittent constipation; often used long term for prevention of opioid-induced constipation Oral onset 6–12 hr, suppository within 1 hr; oral tablets are enteric coated Onset 1–2 days (may require multiple doses); associated with gas and bloating; syrup or powder for solution Onset 1–3 days; safe in renal and hepatic disease and pregnancy; overall, well tolerated; may be used long term Dose: Measure 20 g of powder into a glass. Add 4 to 8 ounces of water or other common beverage (juice, coffee, tea, soda) and stir to dissolve. Drink the entire contents of the glass once daily. If persistent loose stools occur, reduce the daily dose to 10 g of powder. Separate lactitol dose from other oral medications by at least 2 hours. Tablet and liquid; onset 6–12 hr; can cause abdominal cramping, electrolyte disturbances, melanosis coli ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-178 Gastrointestinal Disorders Table 29. Drug Therapy Options for Treatment and Prevention of Constipation (continued) Drugs Role Bulk-forming laxatives Psyllium inulin Intermittent or chronic constipation Inulin Wheat dextrin Calcium polycarbophil Methylcellulose Guanylate cyclase-C agonist Linaclotide FDA approved for IBS-C and CIC (Linzess) Comments Onset 12–72 hr; less effective in drug-induced constipation and STC; requires adequate water intake to be effective; several formulations; soluble forms can be incorporated into foods, liquids, and recipes; safe in renal and hepatic disease, pregnancy, geriatrics; can cause gas and bloating. Soluble fiber with low fermentability (i.e., psyllium) is associated with fewer adverse effects such as bloating, flatulence, and abdominal discomfort Guanylate cyclase-C agonist: Increases fluid secretion and transit time 145- and 290-mcg capsules IBS-C: 290 mcg orally once daily; for CIC: 145 mcg orally once daily Plecanatide (Trulance) FDA approved for IBS-C and CIC in adults Take on empty stomach 30 min before meal; common adverse effects include diarrhea, abdominal pain, flatulence, and abdominal distension; contraindicated in pediatric patients < 6 yr and in mechanical obstruction; avoid in patients 6–17 yr of age; pregnancy category C Guanylate cyclase-C agonist; increases fluid secretion and transit time; 3 mg tablet once daily can be crushed and administered in applesauce or water or via feeding tube; common adverse effect is diarrhea; however, significantly less common than with linaclotide Contraindicated in pediatric patients < 6 yr and in mechanical obstruction; avoid in patients 6–17 yr old Peripheral opioid antagonist Methylnaltrexone FDA approved for OIC in palliative care patients and for OIC in adult (Relistor) patients with noncancer pain Peripheral opiate antagonist; will not reverse central analgesia OIC with advanced illness: Subcutaneous injection every other day as needed, dose based on patient weight Onset within 4 hr in about 50% of patients OIC with non cancer pain: Oral tablet 450 mg once daily or 12 mg subcutaneous injection daily ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-179 Gastrointestinal Disorders Table 29. Drug Therapy Options for Treatment and Prevention of Constipation (continued) Drugs Role Peripheral opioid antagonist (continued) Naldemedine FDA approved for OIC in adult patients with non-cancer-related (Symproic) pain who do not require frequent opioid dose escalation Peripheral mu-opioid receptor antagonist Naloxegol Peripheral m-opioid receptor antagonist (Movantik) Alvimopan (Entereg) Serotonin agonist Prucalopride (Motegrity) FDA approved for OIC in adult patients with noncancer pain 0.2 mg once daily Avoid use with strong CYP3A inducers. Monitor for naldemedine toxicity with concomitant moderate and strong CYP3A inhibitors and P-glycoprotein inhibitors 12.5- and 25-mg capsules; adjust dose for CrCl < 60 mL/min/1.73 m2; contraindicated with use of strong CYP3A4 inhibitors or in patients with obstruction FDA approved for accelerating gastrointestinal recovery after surgeries that include partial bowel resection with primary anastomosis Peripheral m-opioid receptor antagonist FDA approved for treating CIC in adults Unlike past serotonin agonists (cisapride, tegaserod), prucalopride is highly selective for GI serotonin receptors and has not been reported to result in cardiac adverse effects. Carries a warning for suicidal ideation Miscellaneous agents Docusate sodium Prevention of opioid-induced constipation in combination with Docusate potassium stimulant laxatives such as senna or prevention of straining in post-MI, postsurgical, and pregnant patients Lubiprostone FDA approved for CIC in adults and for IBS-C in women > 18 yr (Amitiza) Tenapanor (Ibsrela) Comments 12 mg prior to surgery then 12 mg twice daily until discharge, maximum 7 days (15 doses); long-term use associated with myocardial infarction; only available through a REMS program Onset 1–6 days; requires adequate water intake to be effective Chloride channel (ClC-2) activator; results in intestinal fluid secretion; can reduce bloating and abdominal pain; main adverse effect is nausea; dose is 24 mcg twice daily for constipation and 8 mcg twice daily for IBS-C; need negative pregnancy test before use FDA approved for IBS-C in patients Tenapanor is a sodium/hydrogen exchanger 3 > 18 yr inhibitor that results in increased intestinal water secretion and GI transit time. Tenapanor may reduce abdominal pain. It is not recommended in patients < 18 yr and is contraindicated in patients < 6 yr because of risks of serious dehydration CIC = chronic idiopathic constipation; CrCl = creatinine clearance; FDA = U.S. Food and Drug Administration; HF = heart failure; IBS-C = constipation-predominant irritable bowel syndrome; MI = myocardial infarction; OIC = opioid-induced constipation; REMS = Risk Evaluation and Mitigation Strategies; STC = slow-transit constipation. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-180 Gastrointestinal Disorders XI. IRRITABLE BOWEL SYNDROME A. Definition and pathophysiology 1. IBS is considered a functional GI disorder and a disorder of the gut-brain interaction. 2. Definition divides IBS into the following subtypes: a. Diarrhea predominant (IBS-D) b. Constipation predominant (IBS-C) c. Mixed IBS (IBS-M): Features of both IBS-D and IBS-C d. Unclassified (IBS-U) 3. The pathophysiology is thought to involve alterations in both CNS and intestinal pain perception, alterations in GI motility and secretion, and contributions from current or past psychosocial factors, gas retention, and possibly previous GI infection or bacterial overgrowth. a. IBS is more common in women, lower socioeconomic groups, and patients younger than 50 years. b. Patients with IBS have significant reductions in quality of life and use more health care resources. c. A comorbid psychiatric illnesses, such as depression or anxiety, may be present in a sizeable percentage of patients with IBS. 4. Symptoms: In addition to diarrhea or constipation, pain is often a component of all subtypes. Other symptoms (e.g., bloating, distension, spasm, urgency) may be present. These symptoms, together with the Rome IV diagnostic criteria that follow, help distinguish IBS from other functional GI disorders such as CIC. B. Diagnosis 1. Diagnosis is made by exclusion. Rule out other GI causes with a thorough workup. Evaluation of a patient’s pattern of symptoms may provide insight into subtype, although patients may alternate between forms. 2. Several diagnostic criteria and scoring systems have been developed, including the Kruis, Manning, and Rome criteria. a. The Rome IV criteria are used most commonly and are as follows. i. Recurrent abdominal pain, on average, at least one day/week in the last three months, associated with two or more of the following criteria: (a) related to defecation (b) associated with a change in frequency of stool (c) a ssociated with a change in form (appearance) of stool ii. Symptoms should have started at least 6 months before diagnosis b. Guidelines recommend that if other GI diseases are excluded and no alarm features (e.g., weight loss, bleeding, anemia) are present, diagnosis of IBS can be made with confidence. c. The ACG guidelines also recommend: i. Screening for celiac disease in patients with diarrhea symptoms ii. No endoscopy if younger than 45 years and no alarm symptoms iii. No routine food allergy testing unless reproducible symptoms are present C. Treatment strategies 1. Treatment involves a mix of drug, diet, and gut-directed psychotherapy interventions. Cognitive behavioral therapy, dynamic psychotherapy, and hypnotherapy have all shown effectiveness in IBS. 2. Dietary intervention involves avoidance of foods that trigger symptoms. Current guidelines recommend a trial of diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) to reduce global IBS symptoms. Low FODMAP diets consist of 3 phases: restriction for 4-6 weeks, reintroduction of FODMAP foods, and personalized diet based on the results of reintroduction. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-181 Gastrointestinal Disorders 3. Drug therapy should target main symptoms and possible psychiatric comorbidities. Combinations of drugs may be necessary for maximal effectiveness. Treatment often begins with nonpharmacologic and nonprescription therapies. Escalation to symptom-driven prescription therapies may be necessary. Choice of treatment should be based on the efficacy of a treatment for a patient’s symptoms balanced with the tolerability of the therapy such as the likelihood and severity of adverse effects. Treatment of IBS-M should target the current symptoms. Symptoms of pain should be treated with gut-directed therapies listed below. Opioids should be avoided in GI pain disorders of gut-brain interaction. a. Antispasmodics: Used mostly for short-term relief of abdominal pain, but also to treat diarrhea in patients with IBS-D. They can be used on an as-needed or scheduled basis. Anticholinergic antispasmodics are contraindicated in patients with comorbid severe UC, GI or urinary obstructions, myasthenia gravis, and glaucoma. Current guidelines recommend against the use of antispasmodics (dicyclomine and hyoscyamine) for global IBS symptoms due to limited and outdated trial data supporting their efficacy. Guidelines support the use of peppermint oil for global IBS symptom relief. i. Dicyclomine (Bentyl): Anticholinergic adverse effects ii. Hyoscyamine (Levsin, Levsin SL), anticholinergic adverse effects iii. Peppermint oil: Use enteric-coated products; it can worsen GERD, but can improve symptoms in IBS and is superior to placebo. b. Tricyclic antidepressants: Treat pain, improve global symptoms, and slow motility in patients with IBS-D. They can be used in IBS-C but may worsen constipation i. Amitriptyline, nortriptyline, and imipramine are the most studied. ii. Therapy should begin with low doses and slowly titrated to treat IBS symptoms while minimizing adverse effects. Doses should not be increased enough to treat comorbid depression. iii. Potential for anticholinergic effects, sedation, CV effects, and drug interactions. c. SSRIs: Have been used in the past to treat abdominal pain associated with IBS. Current guidelines recommend against the use of SSRIs to treat IBS symptoms because of a lack of strong data to support the benefits of their use. SSRIs can still be used to treat comorbid depression, anxiety, or other mood disorders in the setting of IBS. d. Laxatives can be used for IBS-C. i. Psyllium has the best evidence; however, it can cause bloating and gas formation. Calcium polycarbophil can be used as an alternative bulk-forming agent. Wheat or corn bran should not be used. ii. Polyethylene glycol–based laxatives (MiraLAX) can increase stool frequency, but they have no effect on reductions in abdominal pain and overall symptoms in IBS. There is minimal to no bloating. iii. Avoid stimulant laxatives because they can worsen abdominal pain. e. Lubiprostone (Amitiza) approved by the FDA for IBS-C in women older than 18 years. i. Chloride channel activator; improves motility and possibly pain ii. Dose is 8 mcg twice daily with meals for IBS-C. iii. Nausea and diarrhea are the main adverse effects. Patients should be advised to take lubuprostone with food to minimize nausea. f. Linaclotide (Linzess) is approved for IBS-C. ii. Guanylate cyclase-C agonist: increases fluid secretion and decreases transit time iii. Dose is 290 mcg orally taken once daily on an empty stomach 30 minutes before meals. iv. Common adverse effects: diarrhea, abdominal pain, flatulence, and abdominal distension ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-182 Gastrointestinal Disorders g. Plecanatide (Trulance) is approved for IBS-C. i. Structural analog of uroguanylin, an endogenous guanylate cyclase-C agonist, causes an elevation in intracellular cyclic guanosine monophosphate (cGMP), stimulates secretion of chloride and bicarbonate into the intestinal lumen through activation of the cystic fibrosis transmembrane conductance regulator ion channel. Decreased activity of pain-sensing nerves appears to occur because of elevated extracellular cGMP concentration (clinical relevance of the effect on pain fibers has not been established). ii. Dose: 3 mg daily without regard to food iii. Common adverse effects: Mainly GI related. If severe diarrhea occurs, discontinue plecanatide. iv. Counseling points: May be crushed and administered in applesauce or water, or by feeding tube. Dispensed in a monthly blister pack h. Tegaserod (Zelnorm) is a serotonin-4 partial agonist that is approved by the FDA for IBS-C. i. Improves pain, global symptoms, and motility. ii. Tegaserod has been approved for reintroduction to the U.S. market for adult women younger than 65 with IBS-C. It is recommended for women with one or fewer cardiovascular risk factors who have not responded adequately to secretagogue therapy. iii. Tegaserod is contraindicated in patients with past myocardial infarction, stroke, transient ischemic attack, or angina. It is also contraindicated in patients with a history of ischemic colitis or other intestinal ischemia. iv. Linaclotide, lubiprostone, plecanatide, and tegaserod not only treat constipation symptoms but also have positive effects on global IBS-C related symptoms such as abdominal pain, bloating, and flatulence. i. Loperamide: No effects on global symptoms or pain, but reduces motility and increases stool consistency. May be used as an adjunct to other therapies in IBS-D j. Eluxadoline (Viberzi): (C-IV) FDA approved to treat IBS-D i. Mu opioid receptor agonist ii. Dose is 100 mg PO twice daily. Reduce to 75 mg PO twice daily if no gall bladder, unable to tolerate 100 mg, concomitant OATP1B1 inhibitor (e.g., cyclosporine, gemfibrozil, antiretrovirals [atazanavir, lopinavir, ritonavir, saquinavir, tipranavir], rifampin, eltrombopag), or mild-moderate hepatic impairment. iii. Can cause sphincter of Oddi dysfunction. Contraindications include biliary duct obstruction, alcohol abuse (>3 drinks/day), history of pancreatitis, Child-Turcotte-Pugh class C, severe constipation, or GI obstruction iv. Discontinue therapy if constipation lasts for more than 4 days k. Alosetron (Lotronex): Serotonin-3 antagonist that is approved by the FDA for IBS-D i. Improves global symptoms and reduces motility ii. Associated with the development of colonic ischemia; therefore, available only through manufacturer prescribing program. Reserved for patients who have failed conventional therapy. l. Probiotics: Some evidence to support improvement in global symptoms, bloating, and flatulence; not enough evidence to recommend specific strains. Current guidelines suggest avoiding probiotics for global IBS symptom relief due to a lack of sufficient supporting data. m. Antibiotics: A short course (10–14 days) of nonabsorbable antibiotic can improve global symptoms of IBS, especially bloating in IBS-D. i. Rifaximin 550 mg three times daily for 14 days has FDA approval for IBS-D. ii. Patients who respond to rifaximin and experience recurrent symptoms can receive retreatment with rifaximin. n. Selective serotonin reuptake inhibitors (SSRIs) have been used to treat IBS in the past. Current American Gastroenterological Association guidelines recommend against their use as they do not relieve global symptoms or abdominal pain in IBS-D or IBS-C. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-183