Chloride channel activators: Uses, common brands, and safety info

Constipation is an all-too-common experience, and for some, it is a long-term struggle. Laxatives have traditionally been the treatment of choice, including fiber, stool softeners, stimulant laxatives, and osmotic laxatives. Unfortunately, laxatives do not always produce relief, and out of necessity, pharmacologic options for constipation have broadened in the past two decades. Chloride channel activators are one such newer class, meant for those dealing with persistent constipation. Here, we will discuss chloride channel activators’ utility, mechanism, adverse effects, and expense.

What are chloride channel activators?

A medication class with only a single medication currently, chloride channel activators are intended for daily use in the treatment of certain varieties of chronic constipation. They should be taken on a regular basis and not merely as needed. Amitiza is an oral capsule taken twice daily. It is generally reserved for severe cases when multiple laxative classes have failed.

How do chloride channel activators work?

Chloride channels reside within the cell membranes lining the interior epithelium of the small intestine. More specifically of interest for this article is the chloride channel protein 2 (CLC2) that sits on the apical membrane of the intestinal lining. When activated, this ion channel enhances chloride secretion into the intestinal fluid. Water follows this chloride movement, resulting in a greater volume of intestinal secretions. Ultimately, this increased electrolyte and fluid content of stool permit easier colonic transit. 

Lubiprostone is a prostaglandin derivative or physiologically active lipid compound that acts locally within the small intestine to activate CLC2, producing more frequent and comfortable bowel movements. The effectiveness of lubiprostone for constipation may also derive from the activation of prostaglandin receptors, which can induce contractions of the intestinal smooth muscle.

What are chloride channel activators used for?

• Chronic idiopathic constipation

• Constipation-predominant irritable bowel syndrome (IBS-C)

• Opioid-induced constipation

Constipation

Constipation is not always defined consistently. Individuals often have a different definition of what constipation means to them. Even researchers debate on how best to define the condition. Most often, constipation is defined by experts as bowel movements that have at least two of the following features:

• Fewer than three spontaneous bowel movements per week

• Hard stool more than 25% of the time

• Require straining more than 25% of the time

• Require manual maneuvers to pass

• Are associated with a sense of complete emptying

• Are associated with a sense of obstruction

Chronic idiopathic constipation is a form of functional constipation that has occurred for at least three months with no identifiable cause. Functional constipation varieties have no identifiable anatomic reason or primary disease cause. Treatment of chronic idiopathic constipation may require more than home remedies or standard laxative treatment. At a 24 mcg twice daily dosage, Amitiza has demonstrated in clinical trials that it results in more spontaneous bowel movements per week than placebo (inactive pills). 

Similarly, the effects of this prostone can be helpful when the cause of constipation is the use of opioid pain medicine in the setting of chronic, non-cancer pain. Opioids are a common culprit for constipation based on their inhibition of intestinal peristalsis (rhythmic contractions that propel stool forward). Amitiza can be an important treatment option to offset the intestinal inhibitor effect of opioids.

Constipation in the setting of cystic fibrosis

Without an official Food and Drug Administration (FDA) indication, Amitiza is sometimes used off-label as a second-line treatment for constipation in the setting of cystic fibrosis. Cystic fibrosis is marked primarily by lung disease but is also commonly associated with constipation, related to the absence of a functional cystic fibrosis transmembrane conductance regulator (CFTR) protein within the intestinal epithelial cells. CFTR regulates chloride and fluid flow into the intestine, so a dysfunctional CFTR naturally can cause constipation. Theoretically, chloride channel activators could help to overcome the CFTR dysfunction by using CLC2 to stimulate intestinal chloride secretion and consequently increase intestinal fluid secretion. Supporting this idea is a small amount of study data suggesting that lubiprostone may be of benefit to cystic fibrosis patients with constipation.

Irritable bowel syndrome in women

Irritable bowel syndrome (IBS) is another usage niche for Amitiza. A syndrome consisting of abdominal pain and altered bowel movements, IBS may affect about 15% of the population. The alteration in stooling can be in the direction of diarrhea, constipation, or both. The prevalence of IBS and the constipation-predominant form have both been shown to be higher in women. Amitiza, dosed at 8 mcg twice daily, has shown efficacy for women older than 18 years of age with IBS-C.

Who can take chloride channel activators?

Can men take chloride channel activators?

Chloride channel activators can be an appropriate choice of treatment for men with chronic constipation for unknown reasons or due to opioids. Amitiza is not FDA approved for use in men with IBS.

Can women take chloride channel activators?

All three indications for Amitiza are applicable for women, so they can use this chloride channel activator when these constipation conditions are resistant to laxatives.

Can you take chloride channel activators while pregnant or breastfeeding?

A drug that acts locally within the intestine as it passes through the gastrointestinal tract, Amitiza is only minimally absorbed into the bloodstream. While this fact may mean less exposure to the fetus or breastfed infant, study data on Amitiza use in pregnancy or breastfeeding is lacking. Studies in animals have suggested the potential for adverse effects in pregnancy. Therefore, careful consideration of risk and benefit is advised by most healthcare professionals.

Can children take chloride channel activators?

Amitiza is not approved for use in children.

Can seniors take chloride channel activators?

Seniors can take chloride channel activators, but given the potential adverse events of nausea and diarrhea with the drug class, an individual’s risk of dehydration should be taken into account before starting the medication.

Are chloride channel activators safe?

The FDA has not placed a black box warning on lubiprostone. No recalls are currently in place for lubiprostone, but the FDA’s database can be searched for new recalls. Additionally, lubiprostone is not a controlled substance, according to the Drug Enforcement Administration (DEA).

Restrictions

Chloride channel activators should not be used by anyone with a history of hypersensitivity allergic reactions to a member of the drug class. Lubiprostone is also contraindicated in anyone with severe diarrhea, gastrointestinal obstruction, or moderate to severe hepatic impairment (Child-Pugh classification B or C liver disease).

Common chloride channel activators side effects

The following are common Amitza side effects:

• Nausea or vomiting

• Diarrhea or loose stools

• Abdominal pain or dyspepsia (indigestion)

• Abdominal distension (bloating) or flatulence (gas)

• Headache or dizziness

• Sinusitis, upper respiratory infection, or nasopharyngitis (nose and throat inflammation)

• Urinary tract infection

• Peripheral edema (swelling in lower legs or arms)

• Arthralgia (joint pain) or back pain

• Dyspnea (shortness of breath)

• Fatigue

How much do chloride channel activators cost?

Currently, a one-of-a-kind medicine within the chloride channel activator class, lubiprostone commands a significant price in both its brand name and generic form. Brand-name Amitiza can cost $475 for a one-month supply, compared to $420 for a one-month of generic lubiprostone. To check on a better price, show your pharmacist your SingleCare discount card.