Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 and a chloride channel activator with laxative activity. Upon intake, lubiprostone specifically binds to and activates the type 2 chloride channel (ClC-2) in the apical membrane of the gastrointestinal epithelium. This produces an efflux of chloride ions, thereby drawing water into the gastrointestinal lumen. The resulting increased amounts of intestinal fluid soften the stool, increase motility, and improve bowel movements.
Lubiprostone is a medication used in the management of idiopathic chronic constipation. It is a bicyclic fatty acid (prostaglandin E1 derivative) which acts by specifically activating ClC-2 chloride channels on the apical aspect of gastrointestinal epithelial cells, producing a chloride-rich fluid secretion. These secretions soften the stool, increase motility, and promote spontaneous bowel movements (SBM). It was initially approved by the U.S. Food and Drug Administration (FDA) in 2006 and recommended for use in the by the National Institute for Health and Care Excellence (NICE) in 2014.
Mechanism of Action of Lubiprostone
Lubiprostone acts by specifically activating ClC-2 chloride channels, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A action independent fashion. Activation of ClC-2 chloride channels causes an efflux of chloride ions into the lumen, which in turn leads to an efflux of sodium ions through a paracellular pathway to maintain isoelectric neutrality. As a result, water follows sodium into the lumen in order to maintain isotonic equilibrium, thereby increasing intestinal fluid secretion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby increasing the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Activation of ClC-2 chloride channels may also stimulate the recovery of mucosal barrier function by restoring tight junction protein complexes in the intestine. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium. One approach to the treatment of chronic idiopathic constipation is the secretion of fluid into the abdominal lumen through the activation of chloride channels in the apical membrane of the gastrointestinal epithelium. Lubiprostone is a locally acting chloride channel activator that increases intestinal chloride and fluid secretion without altering sodium and potassium concentrations in the serum.
Indications of Lubiprostone
- Chronic idiopathic constipation
- Occasional constipation
- Opioid-induced constipation
- Constipation, drug induced
- Improve symptoms such as bloating and abdominal discomfort
- Improve stool texture,
- Lessen the need to strain,
- Decrease the feeling of not completely relieving oneself.
- Treatment of opioid-induced constipation
- Treatment of irritable bowel syndrome with constipation (IBS-C)
- For the treatment of chronic idiopathic constipation in the adult population. Also used for the treatment of irritable bowel syndrome with constipation in women who are 18 years of age or older.
Contra-Indications of Lubiprostone
- Gastrointestinal obstruction
- Severe diarrhea
- Pregnancy, function
- Hypersensitivity to the active substance or to any of the excipients
- Bowel obstruction,
- Diarrhea-predominant irritable bowel syndrome.
- Ischemic bowel syndrome
Dosage of Lubiprostone
Strengths: 8 mcg ,24 mcg
Constipation – Chronic
- 24 mcg orally 2 times a day
Irritable Bowel Syndrome
- 8 mcg orally 2 times a day
Patients with Chronic Idiopathic Constipation or Opioid-Induced Constipation
Initial Dose
- Mild Liver Dysfunction (Child-Pugh A): Dose adjustment not required.
- Moderate Liver Dysfunction (Child-Pugh B): 16 mcg orally 2 times a day
- Severe Liver Dysfunction (Child-Pugh C): 8 mcg orally 2 times a day
Patients with IBS-C
- Mild (Child-Pugh A) and Moderate (Child-Pugh B) Liver Dysfunction: Dose adjustment not required.
- Severe Liver Dysfunction (Child-Pugh C): 8 mcg orally once a day
Side Effects of Lubiprostone
The most common
- GI obstruction
- Diarrhea
- Dyspnea
- Nausea
- Diarrhea (that is not severe)
- Heartburn
- Vomiting
- Dry mouth
- A runny nose
- A cough
- Dizziness
- A headache
- Joint pain
- Back pain
- Trouble sleeping
More common
- Diarrhea
- full or bloated feeling or pressure in the stomach
- a headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in the chest
- excessive sweating
- sudden drowsiness or need to sleep
- coughing up blood
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
- decreased amount of urine
Rare
- Anxiety
- change in vision
- chest pain or tightness
- confusion
- a cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- extra heartbeats
- hallucinations
- a headache
- irritability
- lightheadedness
- cold and clammy skin
- fast and shallow breathing
- swelling of your feet, legs, or hands purple spot on your skin caused by internal bleeding
- fast or abnormal heart rate or palpitations
- loss of appetite
- lower back, side, or stomach pain
- mental depression
- muscle pain or cramps
- yellowing of your skin or the whites of your eyes
- upper stomach pain
Drug Interactions of Lubiprostone
Alosetron: (Moderate) Alosetron can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone. However, lubiprostone may cause diarrhea as a side effect, but drug discontinuation alone may resolve the diarrhea.
Anticholinergics: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Antidiarrheals: (Moderate) Antidiarrheals can decrease GI motility. These agents may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone. However, lubiprostone may cause diarrhea as a side effect, but drug discontinuation alone may resolve the diarrhea.
Belladonna; Opium: (Moderate) Opium can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone.
Bumetanide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Calcium Phosphate, Supersaturated: (Moderate) Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should not be combined with additional laxatives or purgatives when being used to evacuate the bowel prior to colonic radiologic examinations or surgery.
Crofelemer: (Moderate) Crofelemer, through its local effects as an antidiarrheal on chloride channels in the intestine, may theoretically antagonize the pharmacologic effects of lubiprostone. In general, it would be illogical to concurrently administer crofelemer in combination with lubiprostone. While lubiprostone may cause diarrhea as a side effect, drug discontinuation alone may resolve the diarrhea.
Dichlorphenamide: (Moderate) Use dichlorphenamide and lubiprostone together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including laxatives. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
Ethacrynic Acid: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Furosemide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Lactobacillus: (Moderate) Lactobacillus can decrease GI motility and may antagonize the effects of drugs used to treat constipation, such as lubiprostone. In general, it would be illogical to concurrently administer antidiarrheals in combination with lubiprostone.
Lactulose: (Major) In general, other laxatives, such as lubiprostone, should not be used concurrently with lactulose, especially during the initial phase of therapy for portal-systemic encephalopathy, because the loose stools resulting from their use may falsely suggest that adequate lactulose dosage has been achieved.
Loop diuretics: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Methadone: (Major) Non-clinical studies have shown that opioids of the diphenylheptane chemical class (e.g., methadone) dose-dependently reduce the activation of ClC-2 by lubiprostone in the gastrointestinal tract. There is a possibility of a dose-dependent decrease in the efficacy of lubiprostone in patients using diphenylheptane opioids. Effectiveness in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established; patients taking methadone during clinical trials for opioid-induced constipation had lower response rates than placebo-treated patients.
Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should not be combined with additional laxatives or purgatives when being used to evacuate the bowel prior to colonic radiologic examinations or surgery.
Solifenacin: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Torsemide: (Moderate) Loop diuretics may increase the risk of hypokalemia especially in patients receiving prolonged therapy with laxatives. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy.
Pregnancy & Lactation of Lubiprostone
FDA Pregnancy Category- C
Pregnancy
There are no or limited data from the use of lubiprostone in pregnant women. Studies in animals have shown reproductive toxicity. Lubiprostone should not be used during pregnancy and in women of childbearing potential not using contraception. Patients who become pregnant or are planning a pregnancy should be advised to consider the risks and benefits of continued Lubiprostone therapy during pregnancy. Lubiprostone had no effect on the fertility and reproductive function of male and female rats
Lactation
It is unknown whether lubiprostone or its metabolites are excreted in human milk. In animal studies, neither lubiprostone nor its active metabolites were detectable in breast milk following oral administration of lubiprostone. However, a risk to the newborns/infants cannot be excluded.
References
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