Why does Clozapine (clozapine) cause constipation?

From the Guidelines

Clozapine causes constipation primarily due to its strong anticholinergic properties, which reduce gut motility and decrease secretions, leading to slower transit of stool through the intestines. When clozapine blocks muscarinic receptors in the gastrointestinal tract, it can lead to severe constipation, potentially causing complications like bowel obstruction or paralytic ileus 1. Additionally, clozapine affects serotonergic and histaminergic pathways, which further impacts bowel function. The medication also causes hypersalivation, which can lead to increased fluid loss through swallowing excess saliva, potentially contributing to harder stools.

Key Points to Consider

• Patients taking clozapine should maintain adequate hydration, consume a high-fiber diet, exercise regularly, and may require stool softeners or laxatives as preventive measures.
• Healthcare providers should monitor for constipation in all patients on clozapine, as this side effect occurs frequently and requires proactive management.
• Prophylactic laxatives are suggested for patients taking clozapine to prevent constipation, as recommended in recent clinical practice guidelines 1.
• History-taking and ongoing vigilance for constipation are crucial when managing patients on clozapine, considering factors such as diet, supplements, medications, and co-morbid non-GI conditions.

From the FDA Drug Label

Severe gastrointestinal adverse reactions have occurred with the use of clozapine, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis

Clozapine causes constipation due to its potent anticholinergic effects, which lead to gastrointestinal hypomotility. This can result in severe complications, including fecal impaction, megacolon, and intestinal obstruction.

• Key factors that contribute to constipation include:
  • Potent anticholinergic effects
  • Gastrointestinal hypomotility
• Consequences of constipation and gastrointestinal hypomotility include:
  • Fecal impaction
  • Megacolon
  • Intestinal obstruction
  • Ischemia
  • Infarction
  • Perforation
  • Ulceration
  • Necrosis 2 2

From the Research

Mechanism of Clozapine-Induced Constipation

• Clozapine impairs gastrointestinal motility due to its anticholinergic and antiserotonergic properties, leading to constipation and potentially severe complications such as bowel obstruction and ischemia 3, 4.
• The anticholinergic properties of clozapine can cause a decrease in gut motility, resulting in delayed gastric emptying, small bowel transit, and colon transit 4.
• The exact mechanism of clozapine-induced constipation is not fully understood, but it is thought to be related to the drug's effects on muscarinic and serotonergic receptors in the gut 3.

Prevalence and Severity of Clozapine-Induced Constipation

• Constipation is a common side effect of clozapine treatment, with studies suggesting that up to 82% of patients may experience some degree of gastrointestinal dysmotility 4.
• Clozapine-induced constipation can be severe and even life-threatening, with reports of fatalities due to bowel obstruction and other complications 5.
• The severity of constipation can vary widely among patients, and subjective reporting of constipation may not always accurately reflect the presence or severity of gastrointestinal dysmotility 4.

Management and Treatment of Clozapine-Induced Constipation

• Various treatments are available for managing constipation, including bulk and fiber products, lubricating agents, stimulants, and osmotic laxatives 6, 7.
• Osmotic laxatives, such as polyethylene glycol 3350 (PEG 3350) and lactulose, are considered effective and safe for both short-term and long-term treatment of constipation 6, 7.
• Stimulant laxatives, probiotics, fiber preparations, enemas, and suppositories may also be used as adjunct therapies in specific clinical scenarios 7.