Prokinetic Agents
So close to FDA approval, yet so far
While prokinetic agents as constipation medication have been shown to have a positive therapeutic effect on chronic constipation, recent attempts to bring several agents to market have not succeeded, failing in either clinical trials or being withdrawn from the market due to side effects. Still, a short discussion is warranted, as a few may yet succeed in passing all FDA tests and becoming available.
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Speeding up the gut
Prokinetic or gastroprokinetic means to having an enhancing effect on gastrointestinal mobility. That is, contents of the gut will be sped up by this type of constipation medication. There is some confusion as to how stimulating laxatives and prokinetic laxatives are different. In fact, their modes of action are similar and overlap. Occasionally one reads or hears that stimulant laxatives exhibit prokinetic properties. One big functional difference between the two is that stimulating laxatives enhance movement through the release of mucous and water into the interior of the gut, but prokinetic constipation medication act directly upon cellular sensors that promote smooth muscle movement. Aside from chronic constipation, prokinetic agents are used occasionally after gastric surgery or during gastric radiology.
Several classes of prokinetics
There are several classes of prokinetic agents. Most of them act upon receptors in the gut that lead to release of acetylcholine or dopamine, either indirectly or directly. For example, the cisapride laxative activates a cellular sensor called 5-HT4, which is a serotonin receptor. Serotonin then becomes released in the gut, which leads to subsequent release of acetylcholine.
Acetylcholine and the gut
What is acetylcholine? The gut is a tissue rich in nerve receptors. Nerves communicate both electrically and chemically, by sending electrical impulses or chemical pulses that can be sensed and acted upon. One such chemical messenger is acetylcholine. While acetylcholine seems to perform many functions as revealed in medical research, one of its most important functions is the stimulation of muscle activity. Therefore constipation medication that increase acetylcholine in the gastrointestinal tract have prokinetic effects and lead to faster stool passage times.
Cardiovascular side-effects
Why are prokinetic constipation medication not often prescribed for constipation treatments? The available medications tend to be stimulating laxatives, water-binding or osmotic laxatives. Prokinetic agents are more rarely used, if at all. It turns out that patients have reported serious side effects of prokinetic medications.
To take as an example, five prokinetic agents cisapride, tegaserod, renzapride, zacopride and prucalopride. Although cisapride and tegaserod have been tested extensively in double-blind, randomized clinical trials and shown to be have a statistically significant positive impact on chronic constipation, reports of heart problems eventually lead to an FDA warning to doctors, and subsequent withdrawal of the medication from the market. Two other compounds in this category, renzapride and zacopride, did not make it through clinical trials. Finally, the compound prucalopride, as of early 2009, made it through several stages of clinical trials with promising results. It is possible that it will become available to patients in the near future.
Sources:
Longo and Vernava, Prokinetic Agents for Lower Gastrointestinal Motility Disorders, Diseases of the Colon & Rectum, 2005
Portenoy, Topics in Palliative Care, Oxford University Press, 2001