Continuing Education Activity

Laxatives are a category of medications frequently used to address constipation and various other gastrointestinal medical conditions. Their primary mechanism involves enhancing digestion and promoting bowel movements, thereby facilitating the process of bodily excretion. Laxatives can provide relief for patients with irritable bowel syndrome with constipation, chronic idiopathic constipation, and opioid-induced constipation. Besides addressing constipation, laxatives are occasionally used to empty the bowels before procedures such as colonoscopies. Osmotic or stimulant laxatives are typically used as the first treatment option for constipation. If they do not effectively manage constipation, prokinetics or secretagogues may be used as the next steps. Laxatives are categorized based on the mechanism of action they exert, including bulk-forming laxatives, osmotic and prokinetic agents, lubricants, stimulants, and other types. 

Notably, laxative therapy is not the sole treatment for constipation. Initial management should involve lifestyle changes, including consuming increased fluids and fiber-rich foods, such as asparagus, broccoli, Brussels sprouts, cabbage, and spinach, into their diet. If constipation persists despite lifestyle modifications, the use of laxatives becomes a viable consideration. The comprehensive approach to treating chronic constipation encompasses patient education, behavior modification, dietary adjustments, and, if necessary, the inclusion of laxative therapy. This activity provides a comprehensive review of laxative classification, mechanism of action, proper administration, monitoring practices, and contraindications necessary for healthcare providers to proficiently address constipation and contribute to the overall well-being of their patients.

Objectives:

• Identify the appropriate laxative classification based on the patient's clinical presentation and underlying conditions to determine the most suitable option for individual patients.

• Implement evidence-based guidelines for the effective and safe use of laxatives in managing constipation.

• Assess patient response to laxative therapy, including first- and second-line agents, and adjust treatment plans as necessary.

• Communicate effectively with patients and coordinate care by integrating lifestyle modifications, patient education, and behavioral interventions alongside laxative therapy for comprehensive and patient-centered outcomes.

Indications

Laxatives are a category of medications frequently used to address constipation and various other gastrointestinal medical conditions. Their primary mechanism involves enhancing digestion and promoting bowel movements, thereby facilitating the process of bodily excretion. Osmotic or stimulant laxatives are typically used as the first treatment option for constipation. If they do not effectively manage constipation, prokinetics or secretagogues may be used as the next steps.[1] 

Laxatives can provide relief for patients with irritable bowel syndrome (IBS) with constipation, chronic idiopathic constipation (CIC), and opioid-induced constipation. Yasser Masri et al have described the prophylactic use of laxatives in intensive care unit (ICU) patients to prevent constipation.[2] Also, O'Brien et al have suggested laxatives during opioid administration in patients with sickle cell disease, particularly in post-surgical patients and younger children.[3] 

Constipation is a common diagnosis that requires proper evaluation and appropriate treatment. Notably, laxative therapy is not the sole treatment for constipation. Initial management should involve lifestyle changes, including consuming increased fluids and fiber-rich foods, such as asparagus, broccoli, Brussels sprouts, cabbage, and spinach, into their diet. If constipation persists despite lifestyle modifications, the use of laxatives becomes a viable consideration. The comprehensive approach to treating chronic constipation encompasses patient education, behavior modification, dietary adjustments, and, if necessary, the inclusion of laxative therapy. 

In addition to alleviating constipation, laxatives are occasionally used to empty the bowels before procedures such as colonoscopies. According to the American Gastroenterological Association's 2023 guidelines, CIC is a common clinical condition affecting approximately 8% to 12% of the US population. Regarding pharmacological interventions, treatment options encompass a range of over-the-counter and prescription medications, such as polyethylene glycol (PEG), magnesium oxide, lactulose, and bisacodyl. Unresponsive CIC may require treatment with lubiprostone, linaclotide, plecanatide, or prokinetic agents.[4]

Mechanism of Action

Laxatives are categorized based on the mechanism of action they exert, as mentioned below.

Bulk-forming laxatives: These agents retain fluid in the stool, increasing stool weight and consistency.[5] Psyllium, dietary fiber, and methylcellulose are common examples. It is important to take ample water for bulk-forming agents to work. Lack of water, in turn, can lead to bloating and cause bowel obstruction.[6]

Osmotic agents: This class of medicines is poorly absorbable and draws water into the lumen of the bowel.[5] Milk of magnesia, lactulose, sorbitol, and PEG are common examples.

Prokinetic agents: Cisapride and tegaserod work as agonists of 5-hydroxytryptamine receptors.[5] They work on intrinsic neurons, releasing acetylcholine and inducing mucosal secretion.[7] However, cisapride has been withdrawn from the market due to concerns about severe cardiovascular adverse effects. Tegaserod is available under new investigational drug processes. Prucalopride is a selective, high-affinity 5-HT₄ agonist.[8] ATI-7505 and velusetrag are agents under investigation as well.[7]

Lubricants: Mineral oil aids the passage of stools by its lubricating action throughout the intestines.[9]

Stimulants: Stimulate the myenteric plexus and the Auerbach plexus, increasing intestinal secretions and motility.[10] They also decrease the absorption of water from the lumen of the bowel.[6] Examples include Bisacodyl, senna, cascara, and sodium picosulfate (SPS). Senna and cascara are present in herbal teas or remedies.[5]

Surface active agents: Docusate lowers the surface tension, which leads to water and fats penetrating the stool.[11]

Guanylate cyclase agonist: Linaclotide induces cGMP, leading to cystic fibrosis transmembrane conductance regulator (CFTR), which, in turn, causes water and electrolyte secretion into the lumen.[12] Plecanatide is also an intestinal secretagogue acting through a similar mechanism.[4]

Chloride channel activator: Lubiprostone, a chloride channel activator, leads to water and chloride secretion into the stool and softer stool consistency.[12]

Peripherally acting mu-opioid receptor antagonists: These drugs are used in opioid-induced constipation and block mu-opioid receptors in the gastrointestinal tract, restoring the function of the enteric nervous system without penetrating the central nervous system. Drugs in this category include naldemedine, naloxegol, and methylnatrexone. The American Gastroenterological Association recommends traditional laxatives as first-line agents and endorses peripherally acting mu-opioid receptor antagonists (PAMORAs) for cases requiring escalation of therapy.[13]

Administration

Available Dosage Forms and Strengths

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

Adult Dosage

Bulk-forming laxatives:

• Psyllium: One tablespoon orally 1 to 3 times daily.

• Methylcellulose: One tablespoon powder or 2000 mg fiber caplets thrice daily.

Osmotic agents:

• Lactulose: For constipation, 10 to 20 g (15 to 30 mL) orally daily; the dose may be increased to 40 g (60 mL) daily. For hepatic encephalopathy, 20 to 30 g (30 to 45 mL) orally every hour to induce rapid bowel movement.

• Sorbitol: 30 to 150 mL orally daily. It can also be administered as a 120 mL (30%) solution rectal enema. 

• Polyethylene glycol: For constipation, 17 g 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 to 4 hours before administering PEG.

• Magnesium sulfate: 2 to 4 teaspoons (approximately 10 to 20 g) of granules dissolved in 8 ounces (240 mL) of water; may repeat in 4 hours. Do not exceed 2 doses per day.

• Glycerin (glycerol): One suppository (2 or 3 g) per rectum for 15 minutes daily.

Stimulant laxatives:

• Bisacodyl: 5 to 15 mg as enteric oral tablets daily. Bisacodyl can also be administered as a 10 mg suppository per rectum one time per day for 15 to 60 minutes. Several studies and review articles have raised concerns about the effectiveness of docusate in preventing constipation; clinical judgment should be based on response to therapy.[14]

• Senna: Available as an 8.6 mg tablet. Administer 1 to 2 tablets orally, 1 or 2 times per day.

Prokinetic agents:

• Tegaserod: 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: Available as 1 mg and 2 mg oral tablets. Administer 1 to 2 tablets orally daily.

Lubricants: 

• Mineral oil: Given in single or divided doses orally to 45 mL in 24 hours. It can also be administered rectally as a single dose (118 mL).

Surface active agents:

• Docusate: Available as 100 mg oral soft gels, 283 mg/5 mL (5 mL) of a rectal enema, and 50 mg/5 mL oral solution. It is given orally as a 50 to 100 mg dose daily to a maximum of 300 mg. In addition, it can be given rectally as 283 mg enema 1 to 3 times a day. Several studies and review articles have raised doubts about the effectiveness of docusate in preventing constipation, with a systematic review concluding that docusate demonstrates no greater efficacy than a placebo.

Guanylate cyclase agonist:

• Linaclotide: Available in 72, 145, and 290 mcg oral capsules. A 72- to 145-mcg dosage is given to patients with CIC daily. In patients with IBS with constipation, 290 mcg is used orally daily.

• Plencatide: Available as a 3 mg tablet. The suggested dosage is 3 mg daily for IBS with constipation and CIC.[4] 

Chloride channel activator:

• Lubiprostone: Available in 8 mcg and 24 mcg oral capsules. For CIC, 8 mcg is given twice daily, and for opioid-induced constipation, a maximum of 24 mcg is used orally twice daily.

PAMORAs:

• Naloxegol: Available in 12.5 and 25 mg tablets. The suggested dosage is 25 mg daily. Reduce dose to 12.5 mg daily in intolerance due to diarrhea or abdominal pain.

• Methylnaltrexone: Available in 2 formulations - tablets and injections. The tablets are in a single strength of 150 mg. The injections are in varying concentrations and available in single-dose vials and pre-filled syringes. The single-dose vials contain 12 mg/0.6 mL of methylnaltrexone, while pre-filled syringes are available in 2 strengths - 8 mg/0.4 mL and 12 mg/0.6 mL. The recommended daily oral dosage for tablets is 450 mg.[15] The injectable form typically involves a subcutaneous administration of 12 mg daily. Additionally, weight-based dosing is advised for adult patients experiencing opioid-induced constipation with advanced illness.[16]

• Naldemedine: Available in 0.2 mg oral tablet. The recommended dose is 0.2 mg daily.[17]

Adverse Effects

While most laxatives are generally safe when used appropriately, they can have adverse effects, as mentioned below. 

• Osmotic agents like lactulose can have adverse effects like bloating, nausea, vomiting, and diarrhea.[10] 

• Stimulant laxatives are known to cause abdominal pain.[4]

• Cisapride was withdrawn from the market after cardiovascular adverse effects, including prolonged QT interval that increases the risk for Torsades de Pointes.[5] 

• Mineral oil can cause aspiration and lipoid pneumonia.[6] 

• Osmotic agents like magnesium can cause metabolic disturbances, especially in the presence of renal impairment. Magnesium excretion depends on renal function and requires caution in chronic kidney disease.[18]

• Osmotic agents result in volume load and should be used with caution in renal or cardiac dysfunction.[19] 

• With prokinetic agents, adverse effects like headache, nausea, and diarrhea have been described.[12] 

• Secretagogues like linaclotide can occasionally cause diarrhea.[12] 

• Long-term stimulant laxative use is correlated with the loss of haustral folds in the colon; this could indicate neuronal or muscular injury caused by these agents.[20] 

• In vitro studies have described stimulant laxatives like senna and bisacodyl as having neoplastic potential, but data are lacking in human studies so far.[21] 

• Naloxegol may lead to severe abdominal pain and diarrhea, necessitating hospitalization. Reported cases include gastrointestinal perforation. However, according to the literature, Naloxegol has a low level of causality with adverse events, including gastrointestinal perforation, seizures, stroke, cardiovascular mortality, and ventricular arrhythmia.[22]

• A cohort study utilized UK Biobank data to explore the relationship between regular laxative use and dementia incidence in adults aged 40 to 69 without prior dementia history. The study revealed that regular use of laxatives increases the risk of all-cause dementia. Increased risk was notably observed among those using multiple or osmotic laxatives.[23]

Contraindications

The contraindications involved with laxatives are provided below.

• Generally, patients with hypersensitivity reactions to any active drug or excipients should avoid a particular medicine.[24]

• Patients should avoid laxatives during pregnancy, and bulk laxatives are considered safe during pregnancy. Stimulant laxatives are considered second-line.[25]

• Contraindications to bulk-forming agents include bedridden patients and those with altered cognition.[26] 

• Psyllium agents are contraindicated in those with allergic reactions.[21]

• Use lactulose cautiously in pediatric patients, debilitated patients, patients with hepatic impairment, and older patients.

• Sorbitol should be used with caution in patients with renal impairment.

• The use of Tegaserod is contraindicated in severe renal and hepatic impairment.[27]

• Prucalopride is contraindicated in patients with intestinal obstruction or perforation, ulcerative colitis, Crohn disease, and toxic megacolon.[28]

• Lubiprostone is contraindicated in patients with intestinal obstruction and patients with severe hepatic impairment.[29]

• The FDA has released a boxed warning for plecanatide. Avoid plecanatide in patients aged 6 or younger due to potential dehydration-related fatalities.[30]

Monitoring

In the ongoing assessment of patients undergoing laxative therapy, it is essential to evaluate the therapeutic effectiveness or any potential failures regularly. Additionally, vigilant monitoring for fissures or hemorrhoids, often associated with chronic constipation, is crucial. Continuous monitoring of serum electrolyte levels is imperative for patients, particularly those with conditions predisposing them to electrolyte abnormalities, especially when using osmotic laxatives over an extended period.[31]

The American Gastroenterological Association recommends monitoring the Bowel Function Index in patients experiencing opioid-induced constipation. This scoring system assists in identifying individuals who have not adequately responded to initial laxative treatments for opioid-induced constipation, signaling the need for therapy escalation.[13]

Toxicity

Laxative abuse is not uncommon and is found in patients with anorexia nervosa or bulimia nervosa and older patients who continue to use laxatives once started for constipation. It also includes patients with surreptitious diarrhea.[32] Patients who misuse laxatives usually complain of diarrhea with alternating constipation, nausea, and vomiting.[33] 

These patients can present with dehydration and electrolyte imbalances like hyponatremia, hypokalemia, hyperuricemia, and hyperaldosteronism.[33] Dehydration and hypokalemia together can cause renal insufficiency.[34] In diarrhea, potassium and volume depletion increases aldosterone secretion, worsening hypokalemia.[34] 

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 laxative use. Renal function and electrolytes require careful monitoring. Diuretics can be tapered over 3 months.[35]

Enhancing Healthcare Team Outcomes

Laxatives can effectively treat various medical conditions but may cause adverse effects such as abdominal pain, nausea, and urinary retention. Prescription guidelines for laxative use are crucial for clinicians, as constipation is highly prevalent in outpatient care and requires appropriate patient education. [36][4] Constipation is prevalent in older patients when admitted inpatient and leads to prolonged hospital stays.

Interprofessional healthcare providers, including clinicians, nurses, pharmacists, dieticians, and care staff, should work together to appropriately manage laxative use in patients. Various interventions include maintenance of stool charts, medication review, and medication compliance to manage functional bowel movements during hospitalization.[37] Pharmacists also play a role by reviewing medication management and communicating any identified concerns to clinicians. An interprofessional approach involving clinicians, gastroenterologists, pharmacists, and nurses can enhance patient outcomes while reducing the occurrence of adverse drug reactions.