Antidiarrheals Antidiarrheal Agents

Causes of diarrhea (in red) Many bacteria (e.g., Vibrio cholerae) secrete toxins that inhibit the ability of mucosal ente-rocytes to absorb NaCl and water and, at the same time, stimulate mucosal secretory activity. Bacteria or viruses that invade the gut wall cause inflammation characterized by increased fluid secretion into the lumen. The enteric musculature reacts with increased peristalsis. 

The aims of antidiarrheal therapy are to prevent (1) dehydration and electrolyte depletion and (2) excessively high stool frequency. Different therapeutic approaches (in green) listed are variously suited for these purposes. 

Adsorbent powders are nonabsorbable materials with a large surface area. These bind diverse substances, including toxins, permitting them to be inactivated and eliminated. Medicinal charcoal possesses a particularly large surface because of the preserved cell structures. The recommended effective antidiarrheal dose is in the range of 4-8 g. Other adsorbents are kaolin (hydrated aluminum silicate) and chalk. 

Oral rehydration solution (g/L of boiled water NaQ 3.5, glucose 20, NaHCOs 2.5, KQ 1.5). Oral administration of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport of Na+ and glucose (as well as of H2O) through the mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected. 

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 

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An effective antidiarrheal agent that inhibits peristaltic movement is... 

A not uncommon side effect observed with morphine and some of the other narcotic analgesics is constipation due to decreased motility of the gastrointestinal tract. It proved possible to so modify pethidine as to retain the side effect at the expense of analgesic activity. Relief of diarrhea, it will be realized, is a far from trivial indication. Alkylation of the anion from diphenylacetonitrile (95) with ethylene dibromide gives the intermediate, 96. Alkylation of normeperidine (81) with that halide affords diphenoxylate (97), an antidiarrheal agent. 

Pharmacology Difenoxin is an antidiarrheal agent chemically related to meperidine. Atropine sulfate is present to discourage deliberate overdosage. 

Nonspecific antidiarrheal agents may be useful in treating self-limiting diarrhea. Kaolin and pectin or chalk may adsorb noxious compounds but evidence that such adsorbents are effective is unconvincing. Disadvantages can be prolongation of the course of infection and interference with absorption of desired drugs. 

Colestyramine bind bile acids in the large bowel and is an effective antidiarrheal agent when high concentrations of bile acids are the cause of the diarrhea. 

The more widely used paregoric (camphorated opium tincture) is equally effective and is frequently used in combination with other antidiarrheal agents. Codeine also has been used for short-term symptomatic treatment. 

Morphine is the most abundant of the opium alkaloids. It constitutes as much as 15 percent of the plant extract. Morphine has been used as a medicine and narcotic for thousands of years. Therapeutically, morphine has three principal uses as an analgesic for the relief of acute and chronic pain, as a respiratory depressant, and as an antidiarrheal agent. The analgesic properties are morphine s most important clinical use. 

Inhibition of intestinal peristalsis rates among one of the more common effects of morphine that are not directly related to its analgesic activity. The finding that meperidine (21-4) shares this effect led to the development of a highly substituted derivative, diphenoxilate (22-3), that also inhibits intestinal motility and thus acts as an antidiarrheal agent. The side chain in (22-3) is prepared by alkylation of the anion from diphenylacetonitrile with 1,2-dibromoethane to give the bromoethyl... 

The usual dose with all of these antidiarrheal agents is two tablets to start and then one tablet after each diarrheal stool. 

Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. However, these agents should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition. They should be discontinued in patients whose diarrhea is worsening despite therapy. Antidiarrheals are also used to control chronic diarrhea caused by such conditions as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). 

Antidiarrheal agents Bismuth subsalicylate, 524 mg every 30-60 minutes as needed up to 8 doses daily Kaopectate, Pepto- Bismol, various generics Antidiarrheals should not be used if diarrhea is accompanied by fever > 101°F or if blood or mucus is present in stool. Bismuth salts can cause dark discoloration of the tongue and stools. Salicylates are absorbed and can cause tinnitus if coadministered with aspirin. 

Niemegeers, C.J., Lenaerts, F.M., Janssen, P.A. Difenoxine (R 15403), the active metabolite of diphenoxylate (R 1132). 2. Difneozine, a potent, orally active and safe antidiarrheal agent in rats, Arzneimittelforschung 1972, 22, 516-518. 

Prostaglandins have been used intravenously, both for induction of mid-trimester abortion and for induction of labor in cases of intrauterine death. The same adverse effects as described above occur, and are usually very pronounced. Routine premedication with an antiemetic and an antidiarrheal agent significantly reduces gastrointestinal adverse effects. 

Ippoliti C. Antidiarrheal agents for the management of treatment-related diarrhea in cancer patients. Am J Health SystPharm. 1998 55 1573-1580. 

Rhubarb is used traditionally as both a laxative and an antidiarrheal agent (see Chapter 57). 

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. 

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