Antidiarrheal Effects

Opiate preparations, usually given as paregoric, are effective and fast acting antidiarrheal agents. These agents are also useful postoperatively to produce solid stool following an ileostomy or colostomy. A meperidine derivative, diphenoxylate, is usually dispensed with atropine and sold as Lomotil. The atropine is added to discourage the abuse of diphenoxylate by narcotic addicts who are tolerant to massive doses of narcotic but not to the CNS stimulant effects of atropine. 

---

Weakly absorbed aminoisoxazole (636) has reported antidiarrheal effects in pigs without any side effects (77MIP41600). Sulfanilamide isoxazoles have been used to control atrophic rhinitis in newborn swine. 

Opioids. Activation of opioid receptors in the enteric nerve plexus results in inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not Lullmann, Color Atlas of Pharmacology... 

Peripheral effects concern the motility and tonus of gastrointestinai smooth muscie segmentation is enhanced, but propulsive peristalsis is inhibited. The tonus of sphincter muscles is raised markedly. In this fashion, morphine elicits the picture of spastic constipation. The antidiarrheic effect is used therapeutically (ioperamide, p. 

Difenoxin manifests its antidiarrheal effect by slowing intestinal motility. The mechanism of action is by a local effect on the Gl wall. 

Difenoxin is a metabolite of diphenoxylate with antidiarrheal effects similar to the parent drug. Loperamide Imodium) is a piperidine derivative of diphenoxylate, which acts both at the level of the gut and also in the CNS to reduce GI motility. Its use as an antidiarrheal and its potency are similar to those of diphenoxylate. 

Chronic use of codeine leads to tolerance. After repeated use of codeine, a particular dose loses its effect so that a higher dose is needed to provide the desired effect (such as relief from pain or coughing) that a smaller dose originally provided. This loss of sensitivity to a given dose of codeine is known as tolerance. Eventually, tolerance even develops to the euphoric effect ( high ) of codeine, so that the euphoria becomes less intense over time. A patient may also develop a tolerance to some of codeine s other effects, both medicinal and toxic for example, tolerance develops to codeine s analgesic and sedative effects, but not to its constipating (antidiarrheal) effect. 

As previously noted, opioids have significant constipating effects (see Chapter 31). They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most. 

Despite the lack of studies correlating the antidiarrheic activity of crude drugs with the presence of flavonoids, these have been also studied as pure compounds in this regard. The most used assay of antidiarrhoeic activity is the castor oil test, in which diarrhea is induced by the oral administration of castor oil to mice. Different flavonoids have been shown to possess antidiarrheal activity in this test quercetin, kaempferol, morin, myricetin, rutin (i.p.) [117,118], quercitrin (p.o.) [114,119], and tematin (i.p.) [44], all showing a dose-dependent activity in the range between 25 and 100 mg/kg. However, flavonoids are not only able to exert a preventive antidiarrheal effect in this acute model of experimentally-induced diarrhea, but also in chronic models. Thus quercitrin showed beneficial effects in a model of lactose-induced chronic diarrhea in rats, since it reduced the diarrheal output and facilitated colonic mucosal repair in lactose fed [120]. 

Bismuth salicylate has a number of properties contributing to its antidiarrheal effects. This drug may stimulate water and electrolyte absorption from the lower GI tract, thus decreasing fecal fluid loss. In addition, the bismuth component of this compound may have antibacterial effects, and the salicylate component may inhibit the production of prostaglandins that irritate the intestinal lining. The combination of these properties makes this drug fairly effective in... 

Diphenoxylate and its metabolite, difenoxin, are not used for analgesia but for the treatment of diarrhea. They are scheduled for minimal control (difenoxin is schedule IV, diphenoxylate schedule V see inside front cover) because the likelihood of their abuse is remote. The poor solubility of the compounds limits their use for parenteral injection. As anti diarrheal drugs, they are used in combination with atropine. The atropine is added in a concentration too low to have a significant antidiarrheal effect but is presumed to further reduce the likelihood of abuse. 

The well-known antidiarrheal effect of opioids has been therapeutically exploited for many years. Diarrhea involves both an increase in the motility of the gastrointestinal tract and a decrease in the absorption of fluid and thus a loss of electrolytes (particularly sodium) and water. 

Pharmacological studies with selective agonists have shown that opioid control of intestinal electrolyte transport is predominantly mediated by delta opioid receptors [58], while the gastrointestinal propulsion is under the control of mu receptors [59,60]. The antidiarrheal effects of NEP inhibitors, such as acetorphan, the prodrug of thiorphan, have been compared to those of an opiate agonist, loperamide, in a model of castor oil-induced diarrhea in rats. When administered peripherally, they produced a delayed onset of diarrhea with no reduction in the gastrointestinal transit [61,62], as is commonly observed with loperamide [63],... 

Diphenoxylate is a synthetic compound designed to have the antidiarrheal effects of the opiates, but it also retains some less desirable opiate effects. It is generally combined with atropine, as co-phenotrope, which was originally added to the formulation in the hope of preventing misuse, although it can itself cause problems, especially if the combination is intentionally or accidentally used to excess. 

The effects of a preparation containing berberine and the crude herb Geranii Herba on different diarrheal models in mice and the contractions of isolated guinea pig intestinal muscle were studied via comparison with a preparation containing creosote and loperamide. The results suggested that Geranii Herba exerted its antidiarrheal effect via the inhibition of intestinal movement, with the mechanism of action possibly differing from creosote and loperamide [257]. 

Further studies on the antidiarrheal effects of berberine and the crude herb Geranii Herba were undertaken, utilizing different diarrhea models of mice, as well as on the contractions of isolated guinea pig intestinal smooth muscle and rat intestinal peristalsis. The results were compared with those obtained after administration of atropine and papaverine. Berberine significantly inhibited both the castor oil- and BaCl2-induced diarrheas at oral doses higher than 25 mg/kg, but did not inhibit pilocarpine- or serotonin-induced diarrhea even at 250 mg/kg. Berberine inhibited acetylcholine- or BaCl2-induced contractions of the ileum and colon at a concentration of about 10 5 g/ml, and exhibited a noncompetitive inhibition of the contractile response induced by acetylcholine, whereas atropine displayed a competitive inhibition. Finally, berberine inhibited spontaneous intestinal peristalsis [258]. 

Enkephalins are endogenous opioids that are important enteric neurotransmitters. Enkephalins inhibit intestinal secretion without affecting motility. Racecadotril (acetor-phan), a dipeptide inhibitor of enkephalinase, reinforces the effects of endogenous enkephalins on the 5-opioid receptor to produce an antidiarrheal effect. 

List two opioids used for antimssive effects and one used for antidiarrheal effects. 

Diphenoxylate Diphenoxylate is used to treat diarrhea. It is too insoluble to escape the Gl tract. Like morphine, it causes constipation, but diphenoxylate fails to produce analgesia. Antidiarrheal effects can be blocked by narcotic antagonists (Table 3.6). 

Documented effects A dry extract from the aboveground parts, as well as the total proanthocyanidins have antihypoxic, antioxidant, angioprotective, and hypocholesterimic abilities (Aizikov et al. 1986). An ethanolic extract of the aboveground plant parts had antiulcerogenic activity in rats (Amani et al. 2006), and a methanolic extract exhibited an antidiarrheal effect (Atta and Mouneir 2004). 

Further effects on the GIT include antiamoebic and antidiarrheal activities as reported by Tona et al. and by Galvez et al., whereby euphorbia polyphenolic extract inhibited the growth of Entamoeba histolytica at a concentration below 10 pg/ mL, ° and the lyophilized decoction and one of its constituents, quercitrin, displayed antidiarrheal effect in experimental animal models. 

Summer savory oil is also reported to have spasmolytic on rat-isolated ileum as well as in vivo antidiarrheal effects in mice/ ... 

---