Continuing Education Activity

Constipation is a common diagnosis that requires proper evaluation and appropriate treatment. The approach to a patient with chronic constipation includes patient education, behavior modification, dietary changes, and laxative therapy. It is important to note that laxative therapy is not the only treatment for constipation. Initial management of constipation should include lifestyle changes such as increasing fluids and fiber-rich foods such as asparagus, broccoli, Brussels sprouts, cabbage, and spinach. When constipation is not controlled by lifestyle modification, treatment with laxatives should be a consideration. This activity describes the mode of action of various laxatives, including mechanisms of action, pharmacology, adverse event profiles, eligible patient populations, and monitoring, and highlights the interprofessional team's role in managing conditions where laxative therapy is helpful.

Objectives:

• Describe the mechanism of action of various classes of laxatives.
• Review the indications for laxative therapy.
• Summarize the potential adverse event profile for various classes of laxatives.
• Outline interprofessional team strategies for improving care coordination and communication to properly use laxatives to improve patient outcomes.

Indications

Constipation is a common diagnosis that requires proper evaluation and appropriate treatment. It is important to note that laxative therapy is not the only treatment for constipation. The chronic constipation treatment approach includes patient education, behavior modification, dietary changes, and laxative therapy. Initial management of constipation should include lifestyle changes such as increasing fluids and fiber-rich foods such as asparagus, broccoli, Brussels sprouts, cabbage, and spinach. When constipation is not controlled by lifestyle modification, treatment with laxatives should be a consideration.

Osmotic or stimulant laxatives are considered first-line. Prokinetics and secretagogues are the next steps when osmotic or stimulants are unable to control constipation.[1] Laxatives can also be useful in patients with irritable bowel syndrome (IBS), constipation, chronic idiopathic constipation (CIC), and opioid-induced constipation. Yasser Masri et al. have described the prophylactic use of laxatives in the intensive care unit (ICU) patients to prevent constipation.[2] Also, O'Brien et al. have suggested using laxatives during opioid administration in patients with sickle cell disease, particularly in post-surgical patients and even younger children.[3] In addition to alleviating constipation, laxatives are sometimes used to clear the bowels before procedures like colonoscopies.

Mechanism of Action

Types of laxatives are classified by the mechanism of action they exert in the body.

• Bulk-forming Laxatives: These agents retain fluid in the stool and increase stool weight and consistency.[4] Psyllium, dietary fiber, and methylcellulose are common examples. It is important to take ample amounts of water for bulk-forming agents to work. Lack of water, in turn, leads to bloating and can cause bowel obstruction.[5]

• Osmotic Agents: This class of medicines is poorly absorbable and draws water into the lumen of the bowel.[4] Milk of magnesia, lactulose, sorbitol, and polyethylene glycol (PEG) are common examples.

• Prokinetic Agents: Cisapride and tegaserod work as agonists of 5-Hydroxytryptamine receptors.[4] They work on intrinsic neurons, releasing acetylcholine, and inducing mucosal secretion.[6] However, cisapride has been withdrawn from the market due to concerns about severe cardiovascular side effects. Tegaserod is available under investigational new drug processes. Prucalopride, ATI-7505, and velusetrag are agents currently under investigation in this class.[6]

• Lubricants: Mineral oil aid in the passage of stools by its lubricating action throughout the intestines.[7]

• Stimulants: They stimulate the myenteric plexus and the Auerbach plexus, which increase intestinal secretions and motility.[8] They also decrease the absorption of water from the lumen of the bowel.[5] Bisacodyl, senna, cascara, and sodium picosulfate (SPS) are common examples. Senna and cascara are present in herbal teas or remedies.[4]

• Surface Active Agents: Docusate lowers the surface tension, which leads to water and fats penetrating the stool.[9]

• Guanylate Cyclase Agonist: Linaclotide induces cGMP; this leads to cystic fibrosis transmembrane conductance regulator (CFTR), which, in turn, causes water and electrolyte secretion into the lumen.[10]

• Chloride Channel Activator: Lubiprostone, a chloride channel activator, leads to water and chloride secretion into the stool and softer stool consistency.[10]

Administration

Laxatives are usually taken orally or as suppositories. Oral formulations include tablets, capsules, powders, chewable tablets, and liquids. Data presented in this section is from product labeling information.

Bulk-forming Laxatives

• Psyllium: One tablespoon can be given orally one to three times per day.
• Methylcellulose: One tablespoon powder or 2000 mg fiber caplets can be given three times per day.

Osmotic Agents

• Lactulose: For constipation, administer 10-20 g (15-30 mL ) orally once daily; the dose may be increased to 40 g (60 mL) once daily. For hepatic encephalopathy, administer 20-30 g (30-45 mL) orally every hour to induce rapid bowel movement.
• Sorbitol: Administer 30-150 mL orally once daily. It can be administered as a rectal enema 120 mL (30%) solution. 
• Polyethylene glycol: For constipation, administer 17 grams with adequate hydration. When used as bowel preparation before surgery, powder for solution (240 mL reconstituted solution) is given orally every 10 minutes until 4 L is consumed and rectal effluent is clear. The patient should fast for at least 3-4 hours before administering PEG.
• Magnesium sulfate: Use 2 to 4 teaspoons (approximately 10 to 20 grams) of granules dissolved in 8 ounces (240 mL) of water; may repeat in 4 hours. Do not exceed two doses per day.
• Glycerin (glycerol): One suppository (2 or 3 grams) per rectum for 15 minutes one time per day.

Stimulant Laxatives

• Bisacodyl: Administer 5 to 15 mg as enteric oral tablets one time daily.  Bisacodyl can also be administered as a 10 mg suppository per rectum one time per day for 15 to 60 minutes. 
• Senna: It is available as an 8.6 mg tablet. Administer 1 to 2 tablets orally once or two times per day.

Prokinetic Agents

• Tegaserod: It is available as 6 mg oral tablets. One tablet is given orally 30 minutes before a meal twice daily for 4 to 6 weeks of treatment. 
• Prucalopride: It is available as 1 mg and 2 mg oral tablets. Administer one to two tablets orally once daily.

Lubricants

• Mineral oil: It is given as single or divided doses orally to a total of 45 mL in 24 hours and rectally to a total of 118 mL in a single dose.

 Surface Active Agents

• Docusate: It is available as 100 mg oral soft gels, 283 mg/5 mL (5 mL) a rectal enema, and 50 mg/5 mL oral solution. It is given orally as a 50 to 100 mg dose once daily to a maximum of 300 mg. In addition, it can be given rectally as 283 mg enema one to three times a day.

Guanylate Cyclase Agonist

• Linaclotide: It is available as 72 mcg, 145 mcg, and 290 mcg oral capsules. 72 to 145 mcg is given in patients with chronic idiopathic constipation once daily. In the case of patients with IBS and constipation, 290 mcg is used orally once daily.

Chloride Channel Activator

• Lubiprostone: It is available as eight mcg and 24 mcg oral capsules. Eight mcg is given twice daily in CIC, and a maximum of 24 mcg is used orally twice daily in case of opioid-induced constipation.

Adverse Effects

Most laxatives are safe when used appropriately and in patients without contraindications.

• Osmotic agents like lactulose can have adverse effects like bloating, nausea, vomiting, and diarrhea.[8] 
• Stimulant laxatives are known to cause abdominal pain.[8].
• Cisapride was withdrawn from the market after cardiovascular adverse effects, including prolonged QT interval that increases the risk for Torsades de Pointes.[4] 
• Mineral oil can cause aspiration and lipoid pneumonia.[5] 
• Osmotic agents like magnesium can cause metabolic disturbances, especially in the presence of renal involvement. Also, magnesium excretion depends on renal function, and its use requires caution in renal impairment.[4] 
• Osmotic agents result in volume load and should be used with caution in renal or cardiac dysfunction.[11] 
• With prokinetic agents, adverse effects like headache, nausea, and diarrhea have been described.[10] 
• Secretagogues like linaclotide can occasionally cause diarrhea.[10] 
• Long-term stimulant laxative use has correlated with the loss of haustral folds in the colon; this could indicate neuronal or muscular injury caused by these agents.[12] 
• In vitro studies have described stimulant laxatives like senna and bisacodyl as having neoplastic potential, but data is lacking in human studies so far.[13]

Contraindications

• Generally, patients with hypersensitivity reactions to any active drug or excipients should avoid that medicine.
• Patients should avoid laxatives during pregnancy, and bulk laxatives are considered safe during pregnancy. Stimulant laxatives are considered second-line.[14] 
• Contraindications to bulk-forming agents include bedridden patients and those with altered cognition.[15] 
• Psyllium agents are contraindicated in those with allergic reactions.[13]
• Use lactulose cautiously in elderly, pediatric, debilitated patients, and patients with hepatic impairment.
• Sorbitol should be used with caution in patients with renal impairment.
• The use of Tegaserod is contraindicated in severe renal impairment and severe hepatic impairment.[16]
• Prucalopride is contraindicated in patients with intestinal obstruction or perforation, ulcerative colitis, Crohn disease, and toxic megacolon.[17]
• Lubiprostone is contraindicated in patients with intestinal obstruction and patients with severe hepatic impairment.[18]

Monitoring

• Evaluate the patient using laxatives at regular intervals for therapeutic success or failure to evaluate continuation or modification of treatment.
• Monitor for fissures or hemorrhoids that may be caused by chronic constipation. 
• Monitor serum electrolyte levels in patients, especially when using osmotic laxatives chronically or in patients with diseases that make them prone to electrolyte abnormalities.[19]

Toxicity

• Laxative abuse is not uncommon and is found in patients with anorexia nervosa or bulimia nervosa and the elderly who continue to use laxatives once started for constipation. It also includes patients with surreptitious diarrhea.[20] Patients who misuse laxatives usually complain of diarrhea with alternating constipation, nausea, and vomiting.[21] 
• These patients can present with dehydration and electrolyte imbalances like hyponatremia, hypokalemia, hyperuricemia, and hyperaldosteronism.[21] Dehydration and hypokalemia together can cause renal insufficiency.[22] In case of diarrhea, potassium and volume depletion leads to increased aldosterone secretion, which further worsens hypokalemia.[22] 
• The treatment of laxative abuse is to quit the causative agent. The main challenges are rebound symptoms like weight gain, edema, and constipation, which are very distressing for the patient. Edema is due to renal retention of water. Diuretics should be used with caution to help with constipation and edema and increase patient tolerance when stopping the use of the drug. Renal function and electrolytes require careful monitoring. Diuretics can be tapered off over three months.[23]

Enhancing Healthcare Team Outcomes

Constipation is a commonly overlooked problem in clinic visits and inpatient settings, even though it causes significant distress to patients and leads to secondary complications like urinary retention, abdominal pain, and nausea. It is one of the most prevalent outpatient diagnoses among gastrointestinal disorders.[24] The role of specialists like gastroenterologists is to identify which patients need additional testing or specific treatments.[24] Managing constipation includes taking a thorough history and physical examination to look for secondary causes of constipation. It is, however, challenging because there are no universally accepted guidelines. It should involve patient education and setting realistic expectations.

Healthcare staff, including clinicians (MDs, DOs, NPS, and PAs), nurses, pharmacists, dieticians, and care staff, should work together for bowel management while in the hospital. Constipation is very common in the elderly when admitted inpatient and leads to prolonged hospital stays. Various interventions to manage constipation include the nurse maintaining stool charts and the clinician reviewing these charts to revise the laxative dose or switch to another laxative to maintain functional bowel movements while in the hospital.[25] [Level 5] Pharmacists can review the patient chart to verify the dose, drug-drug interactions, and any concerns to the prescriber.  As depicted above, the integrated team approach can result in the best patient outcomes.