Drugs Used in Treatment of Diarrhea (Monogastric)
Therapy for diarrhea includes fluids, electrolyte replacement, maintenance of acid/base balance, and control of discomfort. Antiparasitic drugs or dietary therapy can also play an important role in treatment of some types of diarrhea. Additional therapy may include intestinal protectants, motility modifiers, antimicrobials, anti-inflammatory drugs, and antitoxins (see Table: Antidiarrheal Drugs).
Kaolin-pectin formulations are popular for symptomatic therapy of diarrhea. Kaolin is a form of aluminum silicate, and pectin is a carbohydrate extracted from the rind of citrus fruits. The manufacturers claim that kaolin-pectin acts as a demulcent and adsorbent in the treatment of diarrhea. This action is claimed to be related to the binding of bacterial toxins (endotoxins and enterotoxins) in the GI tract. However, clinical studies have not demonstrated any benefit from administration of kaolin-pectin. It may change the consistency of the feces but neither decreases the fluid or electrolyte loss nor shortens the duration of illness. Nevertheless, it is often administered to small animals, foals, calves, lambs, and kids. Kaolin-pectin products may adsorb or bind other drugs administered PO and reduce bioavailability.
Activated charcoal is derived from wood, peat, coconut, or pecan shells. The material is heated and treated in such a way that many large pores are formed, which dramatically increases the internal surface area. Activated charcoal is available in a variety of pore sizes. The formulations sold for drug and toxicant adsorption typically have pore sizes of 10–20 Å. Activated charcoal is very effective for adsorbing bacterial enterotoxins and endotoxins that cause some types of diarrhea. It also adsorbs many drugs and toxins and prevents GI absorption, so it is a common nonspecific treatment for intoxications. Activated charcoal is not absorbed, so overdose is not a problem.
Although other “mucosal protectants” have questionable efficacy, bismuth subsalicylate is considered by many human gastroenterologists to be the symptomatic treatment of choice for acute diarrhea. Its efficacy has been proved in controlled clinical trials in people with acute diarrhea (enterotoxigenic Escherichia coli or “traveller’s diarrhea”). Bismuth adsorbs bacterial enterotoxins and endotoxins and has a GI protective effect. The salicylate component has antiprostaglandin activity. Practically all of the salicylate is absorbed systemically when administered to dogs and cats. Some animals may dislike the taste of bismuth subsalicylate, and owners should be warned that it will turn the feces black. This may interfere with evaluating the feces for hemorrhage. Salicylate toxicosis is possible, especially in cats.
Anticholinergic drugs are common ingredients in antidiarrheal preparations, because they significantly decrease intestinal motility and secretions. Their parasympatholytic effects decrease segmental and propulsive intestinal smooth muscle contractions and relax spasms of smooth muscle. Although they do not alter the course of the disease, anticholinergic drugs decrease the urgency associated with some forms of diarrhea in small animals, the amount of fluid secreted into the intestine, and abdominal cramping associated with hypermotility. Because few of the types of diarrhea seen in animals can be classified as “hypermotile,” use of anticholinergic drugs is limited in veterinary medicine. Intestinal motility is already impaired in many animals with diarrhea, and these drugs may actually worsen the diarrhea. The anticholinergic drugs also have profound systemic pharmacologic effects. If they are administered in sufficient doses to affect intestinal motility, possible adverse effects include severe ileus, xerostomia, urine retention, cycloplegia, tachycardia, and CNS excitement. Chronic administration may lead to serious intestinal atony.
Atropine is the best known anticholinergic drug, but because it has many other systemic effects, it is not ordinarily used for an antidiarrheal effect. To avoid CNS excitement, quaternary amines such as aminopentamide, isopropamide, and propantheline are preferred, because they do not cross the blood-brain barrier readily.
Hyoscine butylbromide is an antispasmodic and anticholinergic drug that relaxes the smooth muscle of the GI tract. It is approved for treatment of uncomplicated, spasmodic colic in horses. Initial relief of colic pain is seen within 5–10 minutes, with a duration of action of 3–4 hr. Because of its parasympatholytic effects, it causes transient tachycardia; therefore, heart rate monitoring is not an effective indicator of response to treatment for up to 30 min after treatment. It will also decrease gut sounds for 30 min after administration. Rectal relaxation will also make rectal palpation easier. It may also be beneficial in cases of choke, and it will relieve acute bronchoconstriction in horses with recurrent airway obstruction. Hyoscine butylbromide can be administered concurrently with NSAIDs and sedatives.
Opiates have both antisecretory and antimotility effects by action on the µ (mu) and δ (delta) receptors of the GI tract. They decrease propulsive intestinal contractions and increase segmentation for an overall constipating effect. They also increase GI sphincter tone. There is some evidence that opiates inhibit colonic motor activity in horses. In addition to affecting motility, opiates stimulate absorption of fluid, electrolytes, and glucose. Their effects on secretory diarrhea are probably related to inhibition of calcium influx and decreased calmodulin activity. They are frequently used for treatment of diarrhea in dogs, but their use in cats is controversial because they may cause excitement. The constipating effects of morphine and codeine have been known for many years, but they are not used clinically as antidiarrheal drugs. Paregoric is a tincture of opium product and a controlled substance (5 mL of paregoric corresponds to ~2 mg of morphine). Diphenoxylate and loperamide are two synthetic opiates that have specific action on the GI tract without causing other systemic effects. They have been used in small animals and large animal neonates. Diphenoxylate is a controlled substance in a formulation that contains atropine to discourage abuse; at therapeutic doses, there is no effect from the atropine. Opiates can have potent effects on the GI tract and should be used cautiously. Loperamide is available over-the-counter.
Loperamide should not be used in dog breeds known to be sensitive to ivermectin (Collies, Australian Shepherds, Old English Sheepdogs) without genetic testing. These dogs may have a gene mutation (ABCB-1 gene deletion) that causes a functional defect in P-glycoprotein, which controls drug movement in many tissues. In people and genetically normal dogs, large doses of loperamide do not cause the typical CNS effects of opioids, because loperamide does not achieve high concentrations within the CNS because of P-glycoprotein–mediated efflux of loperamide. Dogs with the ABCB-1 gene deletion show signs of ptyalism, panting, ataxia, and recumbency at doses of loperamide that do not affect healthy dogs. These drugs are contraindicated in infectious diarrhea, because slowing GI transit time may increase the absorption of bacterial toxins. In dogs, constipation and bloat are the most common adverse effects. Potentially, paralytic ileus, toxic megacolon, pancreatitis, and CNS effects can develop, especially in cats.
The efficacy of antimicrobials in the therapy of diarrhea is unknown or unproved in most clinical situations. In most cases of diarrhea in small animals, a bacterial etiology is not identified. In large animals, antimicrobial therapy has not been shown to alter the course of bacterial enteritis, and in some cases, is thought to perpetuate the disease by producing “carrier” animals (eg, salmonellosis). Nonabsorbed antimicrobials are frequently combined with motility modifiers, adsorbents, and intestinal protectants in some preparations. Many of these combinations are irrational. Antimicrobials frequently are a treatment for diarrhea in animals, but there are few conditions that have a known etiology for which antimicrobial therapy is indicated. Campylobacter enteritis, from infection with Campylobacter jejuni, is seen in cats and dogs and can be zoonotic. Treatment alleviates clinical signs, but animals usually remain carriers. Suggested antimicrobial therapy includes erythromycin, enrofloxacin, clindamycin, tylosin, tetracycline, or chloramphenicol. Intestinal bacterial overgrowth is usually due to Escherichia coli or Clostridium spp, so therapy is initiated with an oral drug effective in the GI lumen with anaerobic activity (eg, metronidazole, amoxicillin, ampicillin, tylosin, or clindamycin). Equine monocytic ehrlichiosis (see Potomac Horse Fever) is caused by the rickettsial organism Neorickettsia (Ehrlichia) risticii but clinically resembles salmonellosis. Treatment of choice is IV oxytetracycline. Oral doxycycline can be used in mildly affected horses.
Enteritis from a variety of pathogens is common in young animals. When integrity of the intestinal mucosa is lost, septicemia or endotoxemia is likely. Signs of sepsis include severe bloody diarrhea, fever, scleral injection, dehydration, and alteration in the leukogram (early leukopenia in endotoxic shock, followed by leukocytosis). If septicemia or endotoxemia is suspected, systemic antimicrobials are warranted along with NSAIDs. Neonates with diarrhea deteriorate rapidly before culture and sensitivity results are available. Therefore, broad-spectrum antimicrobial therapy should be initiated. Suggested antimicrobials (depending on species) include fluoroquinolones, a penicillin or cephalosporin plus an aminoglycoside (gentamicin, amikacin), ampicillin or amoxicillin, tetracyclines, potentiated sulfonamides, chloramphenicol, or florfenicol. In septic animals, GI absorption is likely to be altered, so parenteral administration is preferred.
The antiprostaglandin activity of NSAIDs may be beneficial with some types of diarrhea and may be important in treatment of septicemia or endotoxemia. Prostaglandins are important intracellular messengers for stimulating hypersecretion by the intestinal mucosa, possibly by stimulating an increase in cAMP. Antiprostaglandin drugs may directly inhibit fluid and electrolyte hypersecretion by the intestinal cells. NSAIDs should be administered cautiously, because they have adverse GI, hepatic, and renal effects.