Reviews for Primary Care - Fall 2007 - (Page 16) Chronic Constipation and Functional Bowel Disorders continued NKCC1 CFTR * * Active Cl secretion ClC-2? K Ca 2 2Cl Cl cAMP cGMP Ca2 Na S K Na Na , K -ATPase or cAMP-activated K channel Increases in second messengers by neurohumoral regulatory agents and pathogenic factors stimulate active anion secretion Figure 4. The mechanism of chloride secretion. Adapted with permission from Chang EB. study conducted by Rubinstein and colleagues examined the prevalence of constipation (defined as any episode of abdominal cramping and decreased stool frequency that responded to oral or rectal laxative therapy) in various age groups of 168 subjects with cystic fibrosis.23 Seventy-three percent of cystic fibrosis patients aged greater than 30 years experienced constipation, an inordinately high prevalence that would suggest that constipation can occur when chloride secretion is impaired because of the mutated CFTR channel. Agents That Stimulate Intestinal Chloride Secretion There are several classes of agents that may stimulate active chloride secretion. A partial list is provided in Table 2.24-26 Available literature suggests that serotonergic agonists (primarily through the 5-HT4 receptor), prostaglandins, and chloride channel activators have the most profound effects on chloride secretion.24,25 Unfortunately, most of the serotonergic second messengers. A second chloride transporter, the type 2 chloride channel (ClC-2), is also believed to be present in the luminal membrane. Therapeutic agents that can affect either or both of these channels have the potential to increase chloride and fluid secretion into the lumen. Chloride Secretion and Colonic Fluid Balance Overall, the small intestine receives approximately 9 liters of fluid per day, approximately 2 liters from oral intake and 7 liters from endogenous secretions.22 Enteric secretions are greatest in the proximal small intestine, where the majority of fluid and electrolyte movements across the mucosa are passive. This property is essential for rapid liquefaction of luminal contents and neutralization of gastric pH. However, more distally, the contribution to overall intestinal secretion by active chloride secretion becomes progressively greater. In the colon, for example, most chloride secretion is likely occurring through chloride channels. Impaired Chloride Secretion in Constipation Although there is no evidence that chloride secretion is impaired in patients with constipation, constipation in patients with cystic fibrosis may result from such a mechanism. A Table 2 Agents That Potentially Stimulate Intestinal Chloride Secretion Agent 5-HT agonist* PGE1* Stool softener Stimulant laxatives Cl channel activator* Drug Name Tegaserod (5-HT4) Misoprostol Docusate sodium Senna, castor oil Lubiprostone Primary Effects Effects on motility ↑ Cl secretion ↓ Na absorption Affects composition of stool Motility stimulant ↑ Cl secretion (ClC-2 agonist) Secondary Effects ↑ Cl secretion ↓ Na absorption Effects on motility ↑ Cl secretion? ↑ Cl secretion ↓ Na absorption? ↓ Na absorption? *Best evidence. Adapted from Wald A; Physicians’ Desk Reference; Medline Plus Web site.24-26 16 VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE
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