Constipation, Diarrhea, and Irritable Bowel Syndrome

Constipation, Diarrhea, Irritable Bowel Syndrome

• Constipation, diarrhea, and irritable bowel syndrome management will be overviewed
• Medications used for constipation, diarrhea, irritable bowel syndrome dosages, side effects, and contraindications will be discussed
• Pharmacotherapy knowledge of medications to patient cases will be applied

Constipation

• Constipation is only a symptom, not a disease
• Typical healthy adults pass 3 or more bowel movements per week
• Constipation can be acute or chronic
• Constipation is a common complaint that may be due to a number of reasons
• It is important to assess secondary etiologies of constipation

Constipation Symptoms

• Major defining characteristics include decreased frequency, hard, dry stool, painful defecation, abdominal distention, and palpable mass
• Minor defining characteristics include rectal pressure, decreased appetite, headache, and abdominal pain
• Red flag symptoms include blood in stools, unexplained weight loss, fever, anorexia, nausea and vomiting

Common Causes of Constipation

• Disease states
• Diabetes Mellitus
• Multiple Sclerosis
• Parkinson's Disease
• Hypothyroidism
• Hypokalemia
• Pregnancy
• Anorexia Nervosa
• Spinal cord injury
• Idiopathic
• Drug Induced

Drug-Induced Constipation

• Opiates, antihypertensives (clonidine, diuretics), ganglionic blockers and vinca alkaloids can induce constipation
• Calcium channel blockers, 5HT3 antagonists, iron supplements, antacids (aluminum, calcium) and sucralfate may cause constipation
• Barium sulfate antihistamines, antidepressants (TCAs) and antipsychotics can induce constipation

Non-Pharmacologic Treatment of Constipation

• Non-pharmacologic treatment is the first line of defense
• It includes dietary modification, specifically increased daily fiber consumption (20-35 gm/day)
• Exercise and increased fluid intake are also part of the first-line defense
• Regular, adequate time devoted to bathroom routine is included

Pharmacologic Treatment of Constipation

• Bulk-forming laxatives
• Surfactants, which act as stool softeners
• Osmotic agents
• Stimulant laxatives
• Opioid-induced constipation agents

Bulk-Forming Laxatives

• Exert their effect primarily by absorbing water and increasing fecal mass
• Increase the frequency and soften stool consistency
• They can be used alone or in combination with increased dietary fiber
• Adverse effects are minimal
• Gas, bloating, and fluid overload are possible adverse effects
• Use caution in fluid-restricted patients

Specific Bulk-Forming Laxatives

• Psyllium (Metamucil) has an onset between 12-72 hours, dosage is up to 1 tablespoon (3.5 gm fiber) up to 3 times per day
• Methylcellulose (Citrucel) has an onset between 12-72 hours, dosage being up to 1 tablespoon (2 gm fiber) or 4 caplets (500 mg fiber) 3 times per day
• Polycarbophil (FiberCon) has an onset between 24-48 hours, dosage of 2 to 4 tabs (500 mg fiber per tab) daily
• Wheat Dextrin (Benefiber) has an onset between 24-48 hours, dosage of 1 to 3 caplets (1 gm fiber) or 2 teaspoonful (3 gm fiber) up to 3 times per day

Surfactants

• There is very little evidence for the use in chronic constipation
• Lower surface tension of stool, allow increased absorption of water into the stool to help soften
• Side effects are few
• Onset 24-72 hours
• Docusate sodium (Colace)-100 mg twice daily; docusate calcium- 240 mg once daily

Osmotic Laxatives

• Increase water content of bowel, stimulating peristalsis
• Hypertonic electrolytes such as magnesium citrate and magnesium hydroxide (Milk of Magnesia) are osmotic laxatives
• Lactulose and Sorbitol are examples of non-absorbable sugars
• Polyethylene glycol (MiraLAX)
• Diarrhea/cramping, dehydration, electrolyte imbalances are possible adverse drug reactions

Specific Osmotic Laxatives

• Polyethylene glycol (MiraLAX) has an onset of 1-4 days and a dosage of 8.5 to 34 grams in 8oz of liquids, side effects of nausea, bloating, cramping
• Lactulose has an onset of 24-48 hours, with a dosage of 10-20 gm (15-30mL) daily, and side effects of abdominal bloating and flatulence
• Sorbitol has an onset of 24-48 hours, with a dosage of 30 gm (230mL of 25% solution) once daily, side effects being abdominal bloating and flatulence
• Glycerin (Glycerol) has an onset of 15 to 60 minutes, with a dosage of 1 suppository per rectum once, with side effects including Rectal irritation
• Magnesium hydroxide (Milk of Magnesia) has an onset of 30 minutes to 3 hours, with a dosage of 30 to 60 mL once daily and side effects of watery stools and urgency and requires caution in renal insufficiency (magnesium toxicity)
• Magnesium citrate has an onset of 30 minutes to 3 hours, with a dosage of 200 mL once and side effects of watery stools and urgency and requires caution in renal insufficiency (magnesium toxicity)

Stimulant Laxatives

• Alter electrolyte transport by intestinal mucosa
• Increase intestinal motor activity, leading to increased motility
• Chronic ingestion may lead to hypokalemia and hyponatremia

Specific Stimulant Laxatives

• Bisacodyl (Dulcolax) has an onset of 6-10 hours, dosage of 1-3 tablets as a single dose (5mg ea), adverse effects may include gastric or rectal irritation
• Bisacodyl (Dulcolax) has an onset of 15-60 minutes if rectal, dosage is 1 suppository rectally (10mg) and adverse effects include gastric or rectal irritation
• Senna(Senokot) has an onset of 6-12 hours, a dosage of 1-2 tablets (8.6mg each) one or two times daily, adverse effects may include melanosis coli

Opioid Induced Constipation (OIC)

• The estimated prevalence is 40-95% in patients with chronic non-cancer pain
• It May develop with longer duration of opioid use
• According to Rome IV (2016), OIC is a change, when initiating opioid therapy, from baseline bowel habits and defecation patterns characterized by reduced bowel frequency, development/worsening of straining, sense of incomplete evacuation, and patient's perception of distress related to bowel habits

Pathophysiology of OIC

• Opioid receptors are throughout the ENS and include μ-receptors in the small intestine and proximal colon
• Opioids block release of ACh on ascending excitatory neurons and inhibit contractions during peristalsis
• Descending neurons inhibit release of nitric oxide (NO) leading to inhibited relaxation during peristalsis

AGA Guidelines On Constipation

• In patients with OIC, the AGA recommends use of traditional laxatives as first-line agents (strong, moderate quality of evidence)
• In patients with laxative refractory OIC, the AGA recommends naldemedine over no treatment (strong, high quality of evidence)
• In patients with laxative refractory OIC, the AGA recommends naloxegol over no treatment (strong, moderate quality of evidence)
• In patients with laxative refractory OIC, the AGA suggests methylnatrexone over no treatment (conditional recommendation, low quality of evidence)
• In patients with OIC, the AGA makes no recommendation for the use of lubiprostone (no recommendation, evidence gap)

OIC Treatment

• Lifestyle changes, which include increasing fiber and fluid intake and exercise, are included
• Stimulant laxatives and stool softeners are equally recommended based on patient preference and efficacy
• Laxatives should be initiated with opioid treatment to prevent OIC
• Bisacodyl or senna +/- docusate are commonly used
• Bisocodyl 5-15mg once daily, senna 8.6mg once or twice daily, docusate 100mg twice daily

OIC Prescription Medication Options

• Prescription medication options should be used when the combination of diet, lifestyle, and OTC laxatives and stool softeners is insufficient to relieve OIC
• Four prescription products are approved for OIC in adults with chronic noncancer pain: lubiprostone, methylnaltrexone, naloxegol, and naldemedine
• Methylnaltrexone, naloxegol, and naldemedine are PAMORAS (peripherally acting mu-opioid receptor antagonists)

Lubiprostone (Amitiza)

• Amitiza is an intestinal secretagogue that activates a chloride ion channel, increasing the absorption of fluids into the intestine
• Amitiza's dose is 24 mcg BID w/ food and water
• ADEs include nausea, diarrhea, and syncope
• Hypotension may occur with the first dose
• Renal adjustment is not needed
• Hepatic impairment requires adjustment
• Should not be used by patients taking methadone

PAMORAs

• PAMORAs block mu opioid receptors in the gut, but do not cross BBB or affect analgesia in CNS
• They have a small risk of opioid withdrawal
• Avoid use of other opioid antagonists
• Patient must be on opioid therapy for at least 4 weeks before starting
• Laxatives should be discontinued prior to PAMORA initiation
• Contraindicated in pts with GI obstruction

PAMORAs Overview

• Methylnaltrexone (Relistor)'s dose is 450mg (3 tablets) on an empty stomach 30 minutes before 1st meal or 12 mg SubQ daily and is hepatically and renally dose is adjusted with abdominal pain, N/V/D, hyperhidrosis, chills as adverse effects
• Naloxegol (Movantik) is 25mg once daily on an empty stomach, with ABD pain, N/V/D, flatulaence as adverse effects; avoid use in severe Hepatic impairment
• Naldemedine (Symproic) is 0.2 mg once daily, abdominal pain, N/V/D as adverse effects; avoid use in severe Hepatic impairement

Diarrhea

• Diarrhea is a symptom of a disease, not a disease itself
• Diarrhea is marked by increased frequency, decreased consistency of fecal discharge, abdominal cramping, rectal urgency, loose, watery, or semi-formed stools
• Diarrhea can be acute or chronic and is usually self-limiting
• Severe cases may lead to water/electrolyte disturbances, acid-base disorders, cardiovascular collapse, and death

Causes of Diarrhea

• Infections (viral acute gastroenteritis, Rotavirus), bacterial acute diarrhea (Clostridium difficile, E. coli, Shigella, Salmonella), and protozoal infections
• Medications, including antibiotics (-Metformin) and laxatives (-Colchicine)
• Inflammation due to ulcerative colitis or from irritable bowel syndrome
• Foods/lactose intolerances

Therapeutic Goals With Diarrhea

• The primary treatment goal involves the prevention of excess water loss and of electrolyte or acid-base disturbances
• Oral rehydration solutions or salts, symptomatic relief, and management of diet are included
• The underlying causes should be treated if possible

Pharmacologic Treatments

• Oral rehydration
• Antimotility agents
• Adsorbents
• Antisecretory agents

Oral Rehydration

• Oral rehydration is the preferred first line of treatment for fluid and electrolyte losses caused by diarrhea due to gastroenteritis as it will treat hypovolemia
• Oral rehydration treatment is independent of age, causative agent, or initial sodium levels with a need an equimolar concentration of glucose and sodium with osmolality 200-310 mOsm/L
• Oral rehydration salts (dissolve in water) and Oral rehydration preparations (Pedialyte) may be used

Antimotility Agents

• Are typically opiates and derivatives: loperamide, diphenoxylate/atropine, tincture of opium, paregoric opium
• Delay transit of intraluminal contents and prolong fecal contact and absorption in GI tract
• Avoid in patients with clinical features suggestive of infectious diarrhea (fever, bloody or mucoid stools)

Loperamide (Imodium)

• It May be used cautiously in patients with no fever/ low grade fever and in whom bloody stools are absent
• Dose: 2 tablets/capsules (4mg) initially, then 2mg after each unformed stool; max dosage of 16mg/day
• Should be used for no more than 2 days
• Adverse effects include constipation, abdominal cramps, and nausea; as well as CNS effects causing drowsiness, dizziness, and euphoria in large doses
• Black box warning: Torsades de pointes, cardiac arrest, and death has been reported with higher than recommended doses

Diphenoxylate/Atropine (Lomotil)

• Is a Schedule IV medication and requires a DEA license to prescribe
• Improvement should be seen within 48 hours, discontinue therapy if no improvement is seen within 10 days at the maximal dose
• Dose: 2 tablets (2.5mg/0.025mg per tablet) four times daily; max dose of 20mg diphenoxylate per day
• ADR: flushing, tachycardia, CNS depression, urinary retention, constipation

Adsorbents

• Used for symptomatic relief
• Absorbs excess fluid in the intestine and stabilizes stool mass
• Onset: 12 hours to 2 days
• Calcium polycarbophil (FiberCon): 1250mg (2 tablets) 1 to 4 times per day
• Safe and well tolerated but has minimal effectiveness

Antisecretory Agents

• Prevent secretions into the bowel and are antimicrobial.
• Bismuth Subsalicylate (PeptoBismol, Kaopectate) can be used with a dosage of 30mL or two tablets every 30 minutes for 8 doses
• Should be used for 2 days or less
• ADR: fecal or tongue discoloration (greyish black)
• Potential for salicylate toxicity (especially in those who take aspirin or are pregnant)

Irritable Bowel Syndrome

• A chronic disorder of the GI tract that is characterized by chronic abdominal pain and altered bowel habits
• Absence of any identifiable cause
• Often a diagnosis of exclusion
• 10-15% of adults have symptoms consistent with IBS

Clinical Presentation

• Recurrent abdominal pain that occurs at least 1 day/week in the last 3 months associated with ≥ 2 of the following: related to defecation, associated with a change in frequency of stool, and/or associated with a change in consistency of stool
• Symptoms began at least 6 months ago

Subtype Determination

• Subtypes guide pharmacotherapy decisions.
• Rome IV most widely used symptom-based diagnostic criteria
• Patients keep diet history and stool diary using Bristol stool form scale (BSFS)
• IBS-C: constipation is the predominant symptom, BSFS type 1 or 2
• IBS-D: Diarrhea is the predominant symptom, BSFS type 6 or 7
• IBS-M: Mixed constipation and diarrhea, >25% of BMs are type 1 or 2 AND >25% of BMs are type 6 or 7

IBS Stool Charts

• Includes the stool types indicating severe constipation, mild constipation, normal, lacking fiber, mild diarrhea, and severe diarrhea based on consistencies

Alarm Symptoms

• Alarm symptoms: Age over 45 at symptom onset, unexplained weight loss, rectal bleeding, unexplained iron deficiency anemia, family history of colorectal cancer and should prompt GI referral

Treatment Principles

• Regardless of subtype, behavioral interventions and lifestyle modifications are 1st line for all patients including sleep hygiene, stress reduction, cognitive behavioral therapy, and increased physical activity
• Dietary changes are critical to managing IBS symptoms and includes implementing soluble fiber, avoiding gas-producing foods and high fat/fried foods, and reduce intake of caffeine, alcohol, carbonated beverages

IBS-C Treatment Steps

• Step 1: Increased fiber and fluid intake and add bulk-forming laxatives
• Step 2: Osmotic laxatives such as Polyethylene glycol (MiraLAX)
• Step 3: Lubiprostone (Amitiza), Linaclotide (Linzess), Plecanatide (Trulance), Tenapenor (Ibsrela)

BulK-Forming Laxatives For IBS-C

• Dietary changes, behavioral changes, and increasing fiber and fluid intake is the first step
• Add bulk-forming laxatives → AKA 'soluble fiber' such as Psyllium (Metamucil), Methylcellulose (Citrucel), Polycarbophil (FiberCon), Wheat Dextrin (Benefiber)
• Osmotic laxatives and Polyethylene glycol (MiraLAX) are also used

Specific Bul Formining Laxatives

• Psyllium (Metamucil) has an onset between 12-72 hours, dosage is up to 1 tablespoon (3.5 gm fiber) 3 times per day
• Methylcellulose (Citrucel) has an onset between 12-72 hours, dosage of up to 1 tablespoon (2 gm fiber) or 4 caplets (500 mg fiber) 3 times per day.
• Polycarbophil (FiberCon) has an onset between 24-48 hours, dosage of 2 to 4 tabs (500 mg fiber per tab) daily
• Wheat Dextrin (Benefiber) has an onset between 24-48 hours, dosage of 1 to 3 caplets (1 gm fiber) or 2 teaspoonful (3 gm fiber) up to 3 times per day

Lubiprostone

• Lubiprostone is an intestinal secretagogue that activates chloride ion channel to increase absorption fluids into the intestine
• Dose: 8 mcg BID w/ food and water
• Adverse effects include nausea, diarrhea, and syncope; and with initial dose-related hypotension
• It requires hepatic impairment adjustment but no renal adjustment
• Does not appear to treat abdominal pain associated with IBS-C

Guanylate

• Linaclotide (Linzess): Guanylate cyclase agonist that is approved for IBS-C
• Increases secretion of chloride and bicarbonate into the intestinal lumen → increased intestinal fluid increased GI transit improving constipation and abdominal pain
• Dosage: 290 mcg daily, 30 minutes before the first meal
• ADR: Diarrhea, flatulence, headache, abdominal distention, or pain
• Do not use in patients < 18 years

Other IBS - C Guanylate Cyclase Agonists

• Plecanatide (Trulance): Guanylate cyclase agonist approved for IBS-C that Increases secretion of chloride and bicarbonate into intestinal lumen → increased intestinal fluid increased GI transit improving constipation
• Dosage: 3mg once daily, irrespective of meals
• ADE: Diarrhea, flatulence, headache, abdominal distention, nausea
• Do not use in patients less than 18 years or those with GI obstruction

Tenapenor (Ibsrela)

• Last line for IBS-C; only when all other treatments have failed for the condition
• Blocks the sodium/hydrogen exchanger 3 (NHE3) to reduce sodium absorption from small intestine and colon, increasing intestinal lumen water secretion, accelerating GI transit time and softening stool consistency
• Discontinue use after 4-8 weeks if no improvement Adverse effects: diarrhea, flatulence, abdominal distention, dizziness, rectal hemorrhage
• Do not use in patients < 6 years old, safety not well established in patients < 18 years old
• Dosage: 50mg twice daily, irrespective of meals

IBS-D Treatment Steps

• Step 1: Antidiarrheal agents (loperamide)
• Step 2: Bile acid sequestrants (cholestyramine, colesevelam, colestipol)
• Step 3: Alosteron, Antibiotics (rifaxamin), Eluxadoline (Viberzi)

Loperamide (Imodium) For IBS-D

• Dose: 2mg 45 minutes before a meal on regularly scheduled doses with a maximum dosage of 16mg/day
• Should be used in limited doses on an as-needed basis
• It is the only antidiarrheal agent evaluated in RCTs for IBS-D
• The adverse effects of constipation, abdominal cramps, nausea, and CNS effects may cause drowsiness, dizziness, euphoria when taken in a large dose
• Black box warning include torsades de pointes, cardiac arrest, and death when taken at higher recommended doses

Bile Acid Sequestrants

• Up to 50% of patients with IBS-D have bile acid malabsorption
• Bile acids cause diarrhea by stimulating colonic secretion and motility; increasing colonic transit time
• Adverse effects include bloating, flatulence, abdominal discomfort, and constipation
• Cholestyramine's dosage is 4 gm once daily; maximum 36 gm/day or Colesevelam 3.75 gm daily in 1 or 2 divided doses

Alosetron

• Only for female patients with severe symptoms of IBS-D that did not respond to all other conventional treatments
• MOA: 5-hydroxytryptamine-3 receptor (5HT-3) antagonist which decreases colonic motility and secretion, and may improve abdominal pain
• Dose: 0.5mg twice daily, and can be increased to 1mg twice daily after 4 weeks if no response and discontinue altogether if no response to 1mg BID after 4 weeks
• Adverse effects include constipation, nausea, abdominal pain, vomiting, flatulence, GERD, and muscle spasms
• Discontinue immediately in patients who develop constipation/symptoms of ischemic colitis

Rifaximin (Xifaxan)

• Last-line treatment for those who have failed other therapies that continue to experience diarrhea and bloating.
• Dose: 550mg three times daily x 14 days
• ADR: Nausea, dizziness, fatigue, peripheral edema, muscle spasms, athralgia, puritis
• May increase ALT and CPK
• A broad-spectrum oral antibiotic and recommended two-week trial that is approved for up to 3 courses of treatment

Eluxadoline (Viberzi)

• It Should only be used in severe IBS-D that is refractory to medications and is high risk for acute pancreatitis associated with use
• Dosage: 100mg twice daily, but may decrease to 75mg twice daily for patients who cannot tolerate higher dosage and should be administered with food, must renally and hepatically, dose-adjusted
• Adverse effects: constipation, nausea, abdominal pain, vomiting, upper respiratory tract infection and is contraindicated to patients: patients with an history of pancreatitis, severe liver impairment (Child-Pugh Class C), heavy alcohol use, patients without gallbladder
• Discontinue use if no response after 12-week trial

Global IBS Symptom Treatments

• Anticholinergic medications and peppermint oil can be used

Anticholinergic Medications

• Used on an as-needed basis for abdominal pain and bloating
• Initiate only if patient has persistent abdominal pain despite adequate constipation treatment for pts with postprandial abdominal pain, gas, bloating, and fecal urgency as it provides short-term relief, with little Evidence long-term efficacy
• Adverse Effects of 0.125 to 0.25 mg sublingual three to four times daily include Hyoscyamine.

Tricyclic Antidepressants

• Recommended to trial in patients who have persistent abdominal pain despite use of antispasmodics
• Tricyclic antidepressants (TCAs) have anticholinergic properties and slow intestinal transit time
• Inhibit reuptake of serotonin and norepinephrine
• Be cautious of the elderly patients (Beers Criteria)
• Can prolong QTc interval to negative cardiac effects
• Should be avoided for QTc levels over 440 ms and other QTc prolonging medications

Other Considerations For Antidepressants

• Start with lowest dose possible
• Allow 3-4 weeks of therapy before increasing the dosage
• Should be taken at bedtime due to sedating effects

Specific Antidepressants For IBS

• Amitriptyline, starting dose of 10-25mg at bedtime, maximum dose of 100mg as tolerated for IBS use only
• Nortriptyline, starting dose of 10-25mg at bedtime, maximum dose of 75mg as tolerated for IBS use only
• Desipramine, starting dose 5-10mg at bedtime, maximum dose of 30mg as tolerated for IBS use only

Peppermint Oil

• Limited evidence but little harm and well tolerated
• May be beneficial in patients interested in natural remedies, by using enteric coated capsules, antimicrobial and anti-inflammatory effects, and theorized modulation of psychosocial distress, and smooth muscle relaxation