Antidiarrheal agents

Normal propulsion of food through the GI tract is crucial for proper absorption of nutrients and water. If transit time is too fast, diarrhea occurs, resulting in 

Causes of diarrhea. Many bacteria (e.g., Vibrio cholerae) secrete toxins that inhibit the ability of mucosal enterocytes 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. 

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 has a particularly large surface because of the preserved cell structures. The recommended effective antidiarrheal dose is in the range of 4-8 g. Kaolin (hydrated aluminum silicate) is another adsorbent. 

Loperamide is, therefore, the opioid antidiarrheal of first choice. The prolonged contact time for intestinal contents and mucosa may also improve absorption of fluid. With overdosage, there is a hazard of ileus. The drug is contraindicated in infants below age 2 years. 

Antibacterial drugs. Use of these agents (e. g., co-trimoxazole, p. 274) is only rational when bacteria are the cause of diarrhea. This is rarely the case. Note that antibiotics also damage the intestinal flora, which in turn can give rise to diarrhea. 

Astringents such as tannic acid (home remedy black tea) or metal salts precipitate surface proteins and are thought to help seal the mucosal epithelium. Protein denatura-tion must not include cellular proteins, for this would mean cell death. Although astringents induce constipation (cf. Al3+salts, p.170), a therapeutic effect in diarrhea is doubtful. 

Morphine and opiates decrease propulsive contractions and have long been used to arrest diarrhea. They are now often replaced by diphenoxylate and difenoxine, often in combination with atropine. Allergic side effects are unusual. Fixed drug eruption can occur from opium (Welsh 1961) but it is rare. In Sweden a few cases of urticaria, angioedema, exanthema, and purpura have been reported. A preparation containing diphenoxylate and atropine (Retardin) caused urticaria and angioedema in three patients and exanthema in one. 

Neomycin is used to alter the intestinal flora in preparation of the bowel for surgery and in hepatic coma. In patients with allergic contact dermatitis to neomycin it may cause a flare of the skin lesions (Pirila and Rantanen 1960 Ekelund and Moller 1969). Nystatin is effective in eliminating moniliasis. Side effects are rare. A case of fixed drug eruption has been reported (Kandil 1969). 

Halogenated hydroxyquinolines act on microorganisms in the intestinal tract and have been used for traveler s diarrhea. In Japan clioquinol (Vioform) has caused a subacute myelooptic neuropathy (SMON). The oral preparations have therefore been removed from the market in most countries. Clioquinol is still used topically and can cause contact dermatitis. A flare of contact dermatitis after oral intake has been reported (Leifer and Steiner 1951 Domar and Juhlin 1967 Ekelund and Moller 1969). 

Cholestyramin is a basic anion exchange resin which is used to ameliorate watery diarrhea in cases of ileal dysfunction, ileal resection, and vagotomy. It is also used to relieve pruritus due to elevated serum and skin levels of bile salts in patients with intrahepatic cholestasis and to lower cholesterol levels in familial hypercholes- 

Desferoxamine (Desferal) is a chelating agent used to remove excess iron from the body in conditions such as hemochromatosis and in acute iron poisoning. Erythema, probably mediated through histamine release and two cases of urticaria have been described after intramuscular injection (Westlin 1971). After oral treatment no allergic side effects are reported. 

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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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