Tag: constipation

Mechanism of action of lubiprostone

What is the exact mechanism of action of lubiprostone in increasing intestinal motility?

Lubiprostone is a bicyclic fatty acid derived from a metabolite of prostaglandin E1 (PGE1). It is used primarily to treat chronic idiopathic constipation in adults and constipation-predominant irritable bowel syndrome in women. Lubiprostone acts via chloride channels to increase chloride levels in the lumen of the bowel. Water osmotically follows the chloride. The increase in fluid both softens the bowel contents and increases the bulk of the bowel contents stimulating peristalsis.

The peristaltic reflex triggers the peristalsis. The bulk of the bolus in the lumen of the gut mechanically stimulates enterochromaffin (EC) cells to release 5-HT, which activates intrinsic primary afferent neurons (IPANs). The IPANs, in turn activate the myenteric plexus to engage retrograde and anterograde cholinergic pathways. The retrograde pathway releases substance P and acetylcholine to contract the smooth muscle behind the bolus. The anterograde pathway releases nitric oxide and vasoactive intestinal peptide to relax the smooth muscle in front of the bolus. This allows peristalsis to move the bolus forward along the intestinal tract.

However, there is some controversy in the scientific literature over the exact mechanism by which lubiprostone acts on chloride transport (for review, see Wilson and Schey, 2015). It was initially identified as an activator of type 2 chloride channels (ClC-2) on the apical surface of the intestinal epithelium stimulating chloride-rich secretions. However, it has also been shown that lubiprostone likely activates prostaglandin E2 receptor 4 (EP4) to activate the cystic fibrosis transmembrane conductance regulator (CFTR), another major epithelial cell membrane chloride channel. Yet, lubiprostone still appears to be effective in treating constipation in patients with cystic fibrosis, suggesting that other mechanisms are also important. Meanwhile, other evidence emerged that ClC-2 is localised on the basolateral membranes of the jejunal and colonic epithelium and is involved primarily in absorption rather than secretion of chloride. It has been reported that lubiprostone leads to internalisation of basolateral ClC-2 with concomitant trafficking of CFTR and the chloride/ hydrogen carbonate exchanger PAT-1 to the apical membrane. Thus, lubiprostone may result in reduced absorption of chloride via ClC-2 on the basolateral membranes at the same time as increased secretion of chloride via CFTR and PAT-1 on the apical membranes.

Although the exact mechanisms of the effect on chloride remain incompletely understood, it is clear that lubiprostone increases chloride in the lumen of the bowel.

Reference:

Wilson, N. and Schey, R. (2015) Ther Adv Chronic Dis. Mar; 6(2): 40–50.

Does hyperthyroidism cause constipation or diarrhoea?

Hyperthyroidism causes sympathetic overactivation such that many of the symptoms of thyroid storm can be alleviated by beta-blockers. The sympathetic nervous system “fright, flight or fight” response opposes the parasympathetic nervous system “rest and digest” response and shuts down gastrointestinal function. So hyperthyroidism causes constipation, correct? 

Sorry, not correct. Yes, hyperthyroidism can stimulate overactivation of the sympathetic nervous system. Yes, symptoms of thyroid storm can be treated with sympatholytic beta-blockers. But no, hyperthyroidism does not cause constipation. Hyperthyroidism causes diarrhoea.  Conversely, hypothyroidism causes constipation.

So, next, you will ask “What is the mechanism?”. Unfortunately, the mechanism is not known. Recent reviews have speculated that it might be due to beta-2 adrenoceptor-mediated effects on gastrointestinal motility and secretions (Daher et al., 2015; Kyriacou et al., 2015) but the evidence for this is very limited.  For example, a case report on one patient has suggested that propranolol can control intractable diarrhoea in hyperthyroidism (Bricker et al., 2001) but another study on ten hyperthyroid patients found no effect of propranolol on the gastrointestinal transit time (Bozzani et al., 1985).

For the moment, as we do not know the underlying mechanism, it is just one of those exceptions that you have to remember. In nearly every other respect, hyperthyroidism has a sympathomimetic effect and hypothyroidism has a sympatholytic effect. But for the gastrointestinal system, it is the opposite.

References:

Bozzani A, Camboni MG, Tidone L, Cesari P, Della Mussia F, Quatrini M, Ghilardi G, Ferrar L, Bianchi PA (1985) Gastrointestinal transit in hyperthyroid patients before and after propranolol treatment. Am J Gastroenterol. 1985 Jul;80(7):550-2.

Bricker LA, Such F, Loehrke ME, Kavanaugh K (2001) Intractable diarrhea in hyperthyroidism: management with beta-adrenergic blockade. Endocr Pract. 2001 Jan-Feb;7(1):28-31.

Daher R, Yazbeck T, Jaoude JB, Abboud B (2009) Consequences of dysthyroidism on the digestive tract and viscera. World J Gastroenterol. 15(23):2834-8.

Kyriacou A, McLaughlin J, Syed AA (2015) Thyroid disorders and gastrointestinal and liver dysfunction: A state of the art review. Eur J Intern Med. 26(8):563-71.

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