Chapter 34 Antidiarrheal Agents
Pathogenesis of Diarrhea
When clinical signs are acute and there are no systemic signs of illness, symptomatic therapy often takes precedence over achieving a precise diagnosis. When the duration of clinical signs is chronic (>3 weeks), or if there are systemic signs of illness, a determined effort should be made to achieve a specific diagnosis. Diarrhea in companion animals may develop through one or more pathophysiologic mechanisms,1 but one mechanism tends to predominate.1,2
Small intestinal bacterial overgrowth (SIBO) and Exocrine pancreatic insufficiency (EPI) are the best examples of luminal maldigestion in companion animals. SIBO (or antibiotic-responsive diarrhea) and EPI induce maldigestion, steatorrhea, and diarrhea because of bacterial degradation of pancreatic enzymes (SIBO) or insufficiency of enzyme secretion (EPI). Fat maldigestion and steatorrhea may also result from deficiencies in bile salt secretion (e.g., intra- or extrahepatic cholestasis) or abnormalities in the enterohepatic recirculation of bile salts (e.g., portosystemic vascular shunts).
Atrophy of the villous absorptive surface area occurs with many pathologic processes. Atrophy is caused by accelerated loss of enterocytes or decreased production of enterocytes by stem cells in the crypts. Stem cells retain the ability to reconstitute the overlying mucosa, but regeneration may take days to weeks depending upon the pathologic process. Viral infections (e.g., parvovirus, coronavirus, rotavirus) are the most important causes of damage to villus enterocytes in dogs and cats. Viral enteritides are usually acute, self-limiting infections that resolve over a matter of a few days to 1 to 2 weeks. Villous atrophy may result from immune-mediated processes such as gluten-sensitive enteropathy in the Irish Setter dog,3 or as a consequence of food sensitivity reactions in both dogs and cats.4 Food sensitivity reactions are increasingly recognized as an important cause of villous atrophy, malassimilation, and diarrhea in companion animals. Immunosuppressive drugs (e.g., glucocorticoids, vincristine, azathioprine, cyclophosphamide) may also cause severe villous atrophy. Glucocorticoids are frequently prescribed in the management of inflammatory bowel disease (IBD). Antiinflammatory doses of glucocorticoids appear to have minimal effect on epithelial cell turnover, but immunosuppressive doses may abolish epithelial cell renewal. These effects are usually reversible with discontinuation of therapy.
Enterocyte dysfunction is a common finding in many of the primary gastrointestinal disorders of dogs and cats. Enterocyte dysfunction may be seen with inflammation, infection, malnutrition, malignancy, ischemia, and with certain drug therapies (e.g., misoprostol). Gastrointestinal tract pathology induces enterocyte dysfunction by impeding Cl− transport, the Na+/glucose cotransporter, the voltage-dependent calcium channel, or any other component of the cell’s signal transduction pathways.2
Brush-Border Membrane Maldigestion
SIBO is the major cause of brush-border membrane damage in the canine intestine. Hydrolase and other brush-border transport proteins are degraded by bacteria, particularly anaerobes, during proliferation of small intestinal bacteria. Damage to the brush-border is usually reversible following appropriate antimicrobial therapy. Similar brush-border membrane maldigestion has been documented in canine IBD, but these changes are also readily reversible with resolution of IBD.1,2 A specific brush-border membrane malabsorption has been documented in Giant Schnauzers with cobalamin deficiency and malabsorption.5
Mucosal Barrier Disruption
Just as the stomach has evolved with mucosal barrier properties to reduce the deleterious effects of gastric acidity, the intestine has evolved with mucosal barrier properties to exclude bacterial pathogens and to maintain oral tolerance.6–9 Barrier disruption may be caused by moderate to severe inflammation, ulceration, ischemia, cytotoxic drugs, and certain protein-losing states. Inflammatory mediators such as interferon-γ, tumor necrosis factor-α, and platelet-activating factor mediate some of the effects on mucosal barrier disruption.10
The role of dietary hypersensitivity reactions in the pathogenesis of canine and feline chronic diarrhea is incompletely understood, although recent studies suggest that adverse reactions to food antigens are common in dogs and cats with chronic diarrhea.4 True allergy or immunoglobulin E–mediated reactions appear to be rare in companion animals.4 Food hypersensitivity reactions may evoke more generalized inflammatory responses involving histamine, leukotrienes, prostaglandins, substance P, or 5-HT (serotonin) effects on gastrointestinal absorption, secretion, permeability, and motility.
Inflammation is a major cause of chronic diarrhea in both dogs and cats. Although gut inflammation may be induced by many different inciting causes (e.g., dietary antigens, bacterial pathogens, toxins, neoplasia), experimental studies suggest that the immune response is initiated and sustained as a result of exposure to dietary antigens and/or indigenous gut bacteria. Cellular components (T and B lymphocytes, plasma cells, macrophages) and molecular elements (prostaglandins, leukotrienes, complement, platelet-activating factor, nitric oxide, and oxygen-derived free radicals) contribute to the mucosal inflammatory response. The clinical signs of IBD (diarrhea, vomiting, anorexia) are somewhat related to the severity of the mucosal cellular infiltrates and inflammatory mediators.11,12 (Functional abnormalities, e.g., changes in the permeability or motility of the gut, may contribute to the clinical signs in many animals.)
Intestinal neoplasia may induce diarrhea by several pathophysiologic mechanisms, including obstruction-induced fluid secretion, release of bioactive substances (e.g., histamine with diffuse mast cell disease, 5-HT with intestinal carcinoid, and gastrin with gastrinoma), bacterial proliferation and overgrowth, protein and lipid exudation, and reduction of the normal villous absorptive surface area.
Lymphatic Transport Disorders
Lymphangitis and intestinal lymphangiectasia are the most common lymphatic transport disorders in the dog. Lymphangiectasia is fairly common in the dog, but rare in the cat. Lymphangiectasia may occur as a primary congenital disorder, or more frequently, it may develop secondarily to IBD,13 neoplastic infiltration, or right-sided heart failure.
Multiple Pathophysiologic Mechanisms of Diarrhea
Some diarrheal disorders result from one pathogenic mechanism, but others may have several concurrent pathogenic mechanisms, for example, maldigestion, malabsorption, excessive secretion, changes in permeability, protein and lipid exudation, and disordered motility.2 EPI is often regarded as a classic maldigestive disorder. In the absence of pancreatic enzyme secretion, undigested protein, lipid, or carbohydrate cannot be further absorbed. Affected animals develop diarrhea, steatorrhea, and severe protein-calorie malnutrition. These same animals develop SIBO, gastric acid–induced injury to the intestinal mucosa, cobalamin malabsorption, and hypersecretion of fluid and electrolytes. It is for these reasons that pancreatic insufficient animals may have incomplete response with pancreatic enzyme replacement therapy. Bacterial infection is another example of a diarrheal disorder with multiple pathophysiologic mechanisms. The heat-stable enterotoxin of enteropathogenic Escherichia coli stimulates guanylate cyclase production of cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinases, culminating in secretory-type diarrhea. At the same time, platelet-activating factor, prostaglandins, and leukotrienes produced during bacterial infection may contribute to the malabsorption and disordered motility of E. coli infections.
Specific Therapy of Diarrhea
The best clinical outcomes will be obtained with definitive diagnosis and specific therapy (see Section VI). A cat with intestinal lymphoma, for example, will have a better outcome if it is correctly diagnosed and treated with chemotherapy. Similarly, a German Shepherd dog with diarrhea, steatorrhea, weight loss, and ravenous appetite will have a much better outcome if it is correctly diagnosed with EPI and appropriately medicated with pancreatic replacement enzymes. Table 34-1 outlines other examples of definitive diagnoses and specific therapies.
|Food sensitivity reaction||Dietary modification|
|Parasitic infection||Anthelmintic agents|
|Fungal infection||Antifungal agents|
|Pancreatic insufficiency||Pancreatic enzymes|
|Lymphangiectasia||Dietary fat modification|
|Hyperthyroidism||Chemo- or radiotherapy|
Nonspecific Therapy of Diarrhea
Definitive diagnosis and specific therapy may not be possible in all cases. This is especially true of cases of IBD in which sequential, nonspecific therapy may be needed to control mild to severe clinical signs (Box 34-1).2,11,12,14 The pet owner may not permit a detailed medical investigation, or a definitive diagnosis may not be reached despite a detailed and appropriate medical investigation. In these cases, it would be entirely appropriate to consider nonspecific forms of therapy. The criteria for commencing nonspecific therapy should include: (a) the diarrhea is chronic, frequent, and/or severe; (b) definitive diagnosis is not forthcoming; and (c) the client does not desire definitive diagnosis.2,12,14
Sequential, Nonspecific Therapy in Inflammatory Bowel Disease