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Dr. Stoll - regarding CCK antagonists

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Dr. Stoll - regarding CCK antagonists

Posted by
Paul on May 19, 2001 at 12:07:34:

thsi article is a little technical for me, What do you think?

Xanax type drugs fall into this category. possible SSR's

What can I use naturally Kava perhaps?

Pathophysiology of Gastroesophageal Reflux Disease: New Concepts
Article 1
Effect of atropine on gastro-oesophageal reflux and
transient lower oesophageal sphincter relaxation
in patients with gastro-oesophageal reflux disease.
Lidims I, Cheklin H, Mittal RK, Holloway RH. Gut 1998;43:12-16

Summary: The traditional belief is that anticholinergics are contraindicated in gastroesophageal reflux disease (GERD) because they delay gastric emptying, reduce resting lower esophageal sphincter (LES) pressure and impair esophageal clearance by reducing peristalsis and inhibiting salivation. However, in normal subjects and most patients with GERD, most reflux episodes occur via the mechanism of transient LES relaxation. Recent studies by these authors in normal volunteers found that although atropine reduced resting LES pressure, it also markedly inhibited the occurrence of transient LES relaxations, thereby decreasing gastroesophageal reflux events. In the current report, the authors studied 15 patients with reflux disease using a crossover design. Esophageal and LES manometry and pH recordings were made for one hour after a standardized meal with the patient either receiving an atropine infusion or placebo (saline). As expected, atropine significantly reduced basal LES pressure from a mean of 7.1 to 2.9 mmHg. Atropine also reduced the median number of reflux episodes from 5 to 1 per hour. This was largely due to near complete abolition of transient LES relaxations. The authors conclude that atropine inhibits reflux in patients with GERD via inhibition of transient LES relaxations, and that pharmacological control of reflux through control of transient LES relaxations is possible.

Article 2
Endogenous cholecystokinin enhances postprandial gastroesophageal reflux
in humans through extrasphincteric receptors.
Clavé P, Gonzales A, Morano A, et. al. Gastroenterology 1998;115:597-604.
Summary: Previous studies have demonstrated that exogenous cholecystokinin decreases lower esophageal sphincter (LES) pressure and increases transient LES relaxations in humans. In the present study, the authors use cholestyramine to increase endogenous CCK release, and studied the effect of this on postprandial transient LES relaxation in 8 healthy volunteers. Subjects ingested a 181 kcal meal either alone or in combination with 12 grams of cholestyramine while esophageal and LES manometry, esophageal pH and gall bladder emptying were monitored. Cholestyramine ingestion was found to cause a marked increase in endogenous CCK release. This was associated with an increase in gall bladder emptying, reflux episodes, transient LES relaxations and esophageal acid exposure that was reversed by administration of the CCK-A receptor antagonist loxiglumide. Loxiglumide also prevented the decrease in LES pressure induced by cholestyramine. Parallel in vitro studies indicated that CCK-8 contracted human LES muscle strips through a tetrodotoxin-insensitive pathway, without modifying LES relaxations induced by stimulation of intrinsic nerves. The authors conclude that endogenous CCK enhances postprandial gastroesophageal reflux in humans by increasing the rate of transient LES relaxations and reducing postprandial LES pressure. The actions appear to be mediated by extrasphincteric CCK-A receptors that override a direct excitatory effect of CCK on the LES muscle.


Ever since Dodds and colleagues identified transient relaxations as the major mechanism whereby gastroesophageal acid reflux occurs, there has been intense interest in the mechanisms whereby these transient LES relaxations occur. LES relaxation is the normal physiological response to swallowing or esophageal distention. It also occurs with belching and vomiting. In the mid 1980's, we demonstrated that LES relaxation was the most sensitive component of the peristaltic reflex and could be activated by pharyngeal or esophageal stimuli that were below the threshold for activating the full peristaltic response. It was subsequently demonstrated that the gastric distention was also a potent stimulus for transient LES relaxation. Clearly, selective pharmacological manipulation of the transient LES relaxation is a logical approach to drug development for GERD. However, the trick has been to inhibit transient LES relaxations without affecting swallow-induced relaxation. Otherwise, we would likely replace a patient's heartburn with dysphagia!

The two studies summarized above demonstrate that transient LES relaxations can be modified by drugs acting at extrasphincteric sites, without affecting swallow-induced LES relaxation. It appears that the effect of atropine is central in that the drug does not alter swallow-induced LES relaxation or LES relaxation induced by electrical stimulation of muscle strips. Furthermore, unlike atropine, the quaternary anticholinergic agent hyocine butyl bromide, which does not cross the blood brain barrier, does not inhibit transient LES relaxations in normal subjects. The site of action of the CCK-A antagonist loxiglumide is uncertain, but based on the study by Clavé et. al. also appears to be extrasphincteric. However, in separate experiments it was demonstrated that intracerebroventricular administration of CCK receptor antagonist did not modify the rate of transient LES relaxations induced by gastric distention in dogs. In animal models it has been demonstrated that CCK influences the LES via its effect on gastric mechanoreceptors and vagal afferent fibers. This may well be the site of action of loxiglumide in the current report.

Although these studies demonstrate that antimuscarinic agents and CCK-A receptor antagonists can inhibit transient LES relaxations thereby decreasing reflux events, it is unlikely that these specific agents will be useful in the treatment of gastroesophageal reflux disease. The inhibitory effect of antimuscarinic agents on salivation, esophageal peristalsis and gastric emptying would likely outweigh any beneficial effect produced by inhibition of transient LES relaxations. Loxiglumide, in addition to inhibiting transient LES relaxations, also markedly impair gall bladder emptying and pancreatic secretion. Therefore this drug might eliminate reflux at the expense of producing maldigestion and gallstones. These studies nevertheless make an important contribution to our understanding of the pathophysiology of transient LES relaxations and provide a foundation for the development of other agents that more selectively target the transient LES relaxation.

William G Paterson, MD, FRCPC
Queen's University

Re: Dr. Stoll - regarding CCK antagonists (Archive in GERD.)

Posted by Walt Stoll on May 21, 2001 at 07:22:28:

In Reply to: Dr. Stoll - regarding CCK antagonists posted by Paul on May 19, 2001 at 12:07:34:

Thanks, Paul.

Just a fancier (and more expensive) piece of black tape!

NO ONE knows what else this stuff does than help with these symptoms. Only time will tell. Those who use it now are participating in an uncontrolled experiment.


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