I. GENERAL CONSIDERATIONS
A. Gastrointestinal (GI) disease is a common clinical problem where signs of vomiting, diarrhea, and anorexia predominate. Rapid diagnosis is essential for symptomatic or specific therapies to be effective. A complete history and physical examination accompanied by appropriate laboratory tests aid in determining the etiology, location, and severity of the disease or disturbance. Endoscopy and mucosal biopsy are frequently required for diagnosis of chronic GI diseases, such as gastritis, malabsorptive syndromes, or idiopathic inflammatory bowel disease (IBD).
B. Nonspecific therapy
1. Correction of fluid and electrolyte balance. Persistent vomiting or watery small bowel diarrhea produces dehydration, electrolyte loss, and disturbances in acid– base balance that should be corrected by parenteral fluid therapy. With severe vomiting, there is variable loss of sodium, chloride, potassium, hydrogen, and bicarbonate that may cause metabolic acidosis. If the pylorus is obstructed, duodenal bicarbonate is retained while continued loss of gastric chloride, potassium, and hydrogen in the vomitus leads to metabolic alkalosis. Oral fluid and electrolyte replacement may suffice in animals having only mild acute diarrhea or if vomiting is infrequent or absent.
2. Resting of the GI tract. Best practice recommendations suggest that withholding food for 24–48 hours in acute GI disturbances is often effective in dogs and cats. Thereafter, feeding a bland diet often and in small amounts is generally indicated for 3–5 days at which time the original diet is gradually introduced. Potential benefits of dietary restriction include decreased gastric secretions, decreased amounts of osmotically active particles in the gut lumen, and the facilitation of mucosal healing (e.g., enterocyte regeneration).
3. Dietary modification
a. Bland diet. A bland, easily digested, low-fat diet such as boiled chicken or white fish or low-fat cottage cheese with rice should be offered after withholding food for 24–48 hours. Limiting dietary fat is important because unabsorbed fatty acids are hydroxylated by colonic bacteria into secretagogues which decrease mucosal absorption and promote increased fecal water loss.
b. Lactose-free diet. Milk products should be eliminated from the diet if there is lactose intolerance or a loss of mucosal brush border lactase from GI disturbances.
c. Insoluble fiber. Increased fiber absorbs water and normalizes intestinal transit in constipation and animals with colitis of diverse causes.
d. Gluten-free diet. Gluten-sensitive enteropathy has been reported to occur in Irish setter dogs. Clinical improvement is observed when affected animals are placed on a cereal-free diet.
4. Provision of nutritional support. Calories, proteins, and vitamins should be supplied to maintain a positive energy and protein balance. Enteral feeding is preferred over parenteral routes since this is most physiologic and prevents atrophy of the intestinal tract. Initial nutrient deficiencies are gauged by use of body condition scores (BCS), and specific nutrient requirements may be estimated by a variety of methods.
5. Symptomatic therapies
a. Protectants and adsorbents. Bismuth-subsalicylate and kaolin-pectin are often administered in acute diarrhea to coat and protect the intestinal mucosa, and because they may reduce intestinal secretions. See more below.
TABLE 11-1. Indications for Antibiotic Use in Gastrointestinal Diseases
| Severe Mucosal Injury |
| – Parvovirus |
| – hemorrhagic gastroenteritis |
| – Salmon poisoning disease |
| Enteropathogenic Bacteria |
| – Salmonella, Clostridia |
| – Campylobacter jejuni, E. coli |
| – Cocci villus adherence |
| Antibiotic-responsive diarrhea (± small intestinal bacterial overgrowth) Inflammatory Bowel Disease |
Note: Antibiotics are uncommonly required in most cases of acute or chronic gastroenteritis. Their specific use is indicated in patients with severe mucosal disruption as evidenced by bloody diarrhea, and in animals diagnosed with specific enteropathogenic bacterial infections or other conditions. Indiscriminate use encourages antibiotic drug resistance and may prolong some types of infectious diarrhea (e.g., salmonellosis).
b. Motility modifying drugs. Opiates and opioids (loperamide, diphenoxylate) are used to decrease intestinal motility and secretions associated with acute diarrhea. Anticholinergics should be avoided since they can potentiate ileus. See more below.
c. Antimicrobial therapy. The routine use of antibiotics for treatment of acute or chronic GI disease is not recommended. Animals having severe mucosal injury (parvoviral enteritis) or infection with specific bacterial pathogens (Campylobacter jejuni) of the GI tract should receive antibiotics. Indiscriminate use of antimicrobials promotes bacterial drug resistance (Table 11-1).
d. Probiotics. These are live bacterial cultures, which promote beneficial microbial health to the host. The mechanism(s) of action are not fully known and their effects appear to be exquisitely host-specific. Preliminary clinical data supports their use as adjunctive therapy for both acute and chronic diarrhea (see below).
e. Analgesics. Indications include alleviation of visceral pain in animals having diverse causes for GI disease (equine colic, pancreatitis in companion animals). Severe visceral pain is alleviated by morphine or opioid receptor agonists that inhibit nociceptive reflexes at spinal and supraspinal sites within the CNS.
(1) Opiates (see Chapter 4 for more information)
(a) Morphine is used in dogs and cats, IM. Its duration of action is 6 hours in these species. High doses of morphine produce excitement in cats and horses and it is administered at 1/10 of the dose used in dogs (0.05–0.2 mg/kg in cats and horses; 0.5–2 mg/kg in dogs).
(b) Butorphanol is administered IV to horses for the control of colic pain. Butorphanol is a partial agonist for μ-receptors and a full agonist for κ-receptors. Its duration of action is 1–2 hours.
(2) Nonsteroidal anti-inflammatory drugs (NSAIDs). (see Chapter 7 for more information) Flunixin meglumine, or phenylbutazone are given IM or IV to horses for the control of colic pain. They inhibit prostaglandin synthesis by inhibiting the enzyme cyclooxygenase. Duration of action is 1–8 hours, depending on the cause and severity of pain.
(3) Sedatives. Xylazine, detomidine, medetomidine, and romifidine are α2-adrenoreceptor agonists, which produce sedation and analgesia in equine colic. Their duration of action is 1–4 hours following IV or IM administration. (see Chapter 4 for more information).
(4) Spasmolytics. N-butylscopolammonium bromide (Buscopan®) is an antispasmodic and anticholinergic drug used in horses for control of the abdominal pain of colic.
(a) Mechanism of action. Bucospan® competitively inhibits parasympathetic activation of muscarinic receptors on intestinal smooth muscle cells.
(b) Therapeutic uses. Bucospan® is administered IV to horses at a dose of 0.3 mg/kg for control of abdominal pain in colic and simple impactions.
(c) Pharmacokinetics. The plasma t½ of Bucospan® is 6 hours. It is eliminated equally via urine and feces.
(d) Adverse effects. Transient tachycardia and decreased borborygmal sounds may be present for 30 minutes following administration. Bucospan® should not be used in impaction colics associated with ileus or in horses with glaucoma.
II. APPETITE STIMULANTS
A. Inappetence or anorexia is common with GI disease. Insufficient nutrient intake delays clinical recovery and may exacerbate the underlying disease. Note that the use of these drugs should be restricted to animals where nutritional intake is measured because of the inconsistent response to their use. Efficacy studies based on controlled clinical trials for use of any of the appetite stimulants is lacking. Enteral alimentation with liquid supplements is quite practical and very useful in small animals.
B. Palatable food. Small amounts of palatable food should be offered at frequent intervals. Warming the food may enhance appetite in carnivores. In general, commercial-derived and nutritionally complete diets should be fed. Homemade diets are quite appropriate for short-term use where the risk of specific deficiencies is minimized by the brief duration of feeding.
C. Benzodiazepines (see Chapter 4 for more information)
1. Mechanism of action. Benzodiazepines may suppress the satiety center in the hypothalamus via increased γ-aminobutyric acid (GABA) activity.
2. Therapeutic uses. Diazepam or oxazepam is used primarily in cats for short-term stimulation of appetite, although the effect is controversial. They are used less frequently in horses, dogs, and goats. Their effectiveness decreases after 2–3 treatments.
3. Administration
a. Diazepam is administered orally, IV (0.2 mg/kg), or IM once or twice a day.
b. Oxazepam is administered orally once a day at 2.5 mg/kg in cats.
4. Adverse effects
a. Sedation and ataxia are common and may be severe in weak or debilitated animals. Reduced dosage should be employed in these cases. Use cautiously in patients with preexisting renal or hepatic disease.
D. Cyproheptadine (see Chapter 3 for more information)
1. Mechanism of action. Cyproheptadine is a serotonin antagonist which suppresses the satiety center in the hypothalamus. It is also a histamine-1 (H1) antagonist and is used as an antiasthmatic in humans.
2. Therapeutic uses. Cyproheptadine stimulates appetite in cats and in humans but not in dogs. It has been used experimentally in cats as an appetite stimulant.
3. Adverse effects. Sedation and dryness of mucous membranes are the most common side effects. Paradoxically, CNS excitement and marked aggressive behavior may occur in 20% of the cats given cyproheptadine.
E. Glucocorticoids
1. Glucocorticoids are frequently employed as appetite stimulants in sick or debilitated animals.
2. Mechanism of action. The mechanism by which glucocorticoids stimulate appetite is unknown. It may be due to euphoria—the increased feeling of well-being produced by glucocorticoids. This is, in part, a result of their anti-inflammatory action.
3. Therapeutic uses. Glucocorticoids are used as nonspecific, short-term therapy for appetite stimulation.
4. Administration
a. Small animals. Prednisolone or prednisone is given once every other day.
b. Large animals. Prednisolone or dexamethasone is given IM once a day.
5. Adverse effects
a. Glucocorticoids are immunosuppressive and may delay recovery from the underlying disease.
b. Decreased gastric mucus production occurs following glucocorticoid administration. Gastric ulcers may develop with high dose or long-term use or in animals where preexisting gastric mucosal disease is present.
III. ANTIOBESITY DRUGS
A. General considerations. Obesity is an important medical condition with serious health implications. Obesity is characterized by the excessive accumulation and storage of fat in the body. Obesity can be defined as exceeding ideal body weight by 20% or more, or BCS of 8 or greater on a 9-point scale. Approximately 20–40% of dogs are considered overweight or obese. The most common cause for obesity is the overconsumption of food combined with inadequate exercise.
B. Dirlotapide (Slentrol®)
1. Mechanism of action. Dirlotapide is a selective microsomal triglyceride transfer protein (MTP) inhibitor that blocks the assembly and release of lipoprotein particles into the bloodstream (via the lymphatic system) in dogs. Its unique mechanism of action provides for potential weight loss by reducing appetite (which accounts for 90% of its clinical efficacy) and by decreasing fat absorption (accounting for about 10% of dirlotapide’s activity).
2. Therapeutic uses. To reduce the obesity in dogs that has been associated with increased risk for development of musculoskeletal disease, hypertension, peripheral insulin antagonism, osteoarthritis, and cardiopulmonary diseases.
3. Pharmacokinetics. Dirlotapide acts locally in the gut to reduce appetite, increase fecal fat, and produce weight loss. Following oral administration, the mean serum t½ is 2.8 hours with bioavailability ranging from 20–40%. There is no clinical effect following IV administration. The variable response between animals and decreasing response over time requires that the dose be regularly and individually titrated to effect. The drug undergoes enterohepatic circulation and is primarily excreted in the feces, with small amounts excreted in the bile and urine.
4. Administration. Dirlotapide is administered once daily as an oil-based solution formulated at a concentration of 5 mg/mL.
5. Adverse effects. The most commonly reported adverse effects include vomiting, diarrhea, anorexia, and lethargy.
IV. DRUGS THAT REDUCE ACID SECRETION AND PROVIDE MUCOSA PROTECTION
A. General considerations. Inhibitors of acid secretion and mucosal protectants are used in veterinary medicine to reduce the hydrochloric acid (HCl) content of the stomach and to promote mucosal healing in animals with ulcers and erosions. The parietal cell possesses receptors for histamine, gastrin, and acetylcholine (ACh)—each of which stimulates H+ secretion into the lumen by the H+/K+-ATPase pump located on the apical membrane. Disease conditions which disrupt the gastric mucosal barrier can lead to endoscopic lesions and clinical signs of GI ulceration or erosion. The fundamental lesion in these instances is the presence of an impaired mucosal barrier which permits the back diffusion of hydrogen ions which causes mucosal ischemia and subsequent damage (Figure 11-1).
FIGURE 11-1. Overview of the etiopathogenesis of gastric ulceration. A common mechanism of H+ back diffusion may occur as a consequence of either endogenous (infiltrative mucosal disease, renal or hepatic disease) or exogenous (NSAID use) disorders. Hydrogen ions present within mucosal tissues promote local vasculitis which causes ischemia and subsequent gastric mucosal disruption.
B. Gastric secretory inhibitors
1. H2-antihistamines (see Chapter 3 for more information)
a. Mechanism of action. H2-antihistamines inactivate H2-receptors of parietal cells. Histamine-evoked gastric secretions are decreased; some (e.g., ranitidine) also have prokinetic activity mediated by their anticholinesterase activity. Ranitidine or famotidine are first-choice agents since they are safe, effective, and have less hepatic inhibition of microsomal metabolizing enzymes than cimetidine. Ranitidine is 3–13 times more potent as cimetidine. Famotidine has greater gastric inhibitory properties and can be given once daily.
b. Therapeutic uses
(1) Ranitidine and famotidine are used to treat gastritis, gastric ulcer/erosions, reflux esophagitis, and gastrinomas (rare) in dogs and cats. Gastric HCl secretion is intermittent in carnivores rather than continuous as in humans; therefore, lower doses are effective. These drugs are also used to treat gastritis and gastric erosions in horses and foals.
(2) H2-antihistamines are used to prevent acid hydrolysis of replacement pancreatic enzymes in exocrine pancreatic disease in dogs and cats.
(3) Cimetidine or ranitidine are used to treat gastritis and gastric erosions in horses and foals.
(4) Ranitidine also stimulates gastric and colonic motility by inhibiting acetylcholinesterase activity. See Section V for additional information
c. Pharmacokinetics. Ranitidine and famotidine are well absorbed orally and widely distributed in body tissues. Only 10–20% of drug is bound to plasma proteins. The plasma t½ is 2–3 hours for ranitidine. Approximately ¼ to ½ of the drug is metabolized by the liver. Metabolites and the parent drug are excreted by the kidneys.
d. Administration
(1) Ranitidine is administered orally, IM, or IV every 12 hours.
(2) Famotidine is administered orally or IV once daily.
(3) Ranitidine may stimulate gastric and colonic motility via its prokinetic activity.
e. Adverse effects. Side effects are rare in animals at usual dosages. Use ranitidine cautiously in animals with impaired renal function. Liver enzyme alanine aminotransferase (ALT) concentrations should be occasionally monitored in animals receiving ranitidine in high doses for greater than 7 days. Some GI effects (anorexia, vomiting, and diarrhea) noted with famotidine. Famotidine has been associated with intravascular hemolysis when given IV to cats.
2. Proton pump inhibitors
a. Mechanism of action (Figure 11-2). Acid pump inhibitors inhibit the H+/K+– ATPase on the luminal (secretory) membrane of parietal cells and thus reduce H+ secretion. Binding to the enzyme is irreversible and restoration of acid secretion requires de novo synthesis of ATPase by the parietal cell. Omeprazole is the protypical agent.
b. Therapeutic uses. Omeprazole is used in the treatment of gastritis, ulcer disease, and esophagitis in dogs, cats, and horses. It is also used in the prevention and treatment of NSAID-induced gastric erosions.
c. Pharmacokinetics. Omeprazole is absorbed orally and enters gastric parietal cells where it is protonated and trapped in the acidic intracellular fluid. The protonated drug is the active form and thus ATPase in nonacid-producing cells is not affected. Since the drug slowly accumulates in parietal cells with repeated doses, pharmacologic action is not correlated with plasma t½. Omeprazole is metabolized by hepatic microsomal enzymes and excreted by the kidney.
d. Administration. Omeprazole is administered orally once a day.
e. Adverse effects. Omeprazole, like cimetidine, inhibits hepatic microsomal (cytochrome P-450) metabolism and may prolong the action of concurrently administered drugs that are metabolized by this system (phase 1 reactions) such as phenytoin or phenobarbital. Use cautiously in animals with preexisting hepatopathy.
FIGURE 11-2. Regulation of gastric acid secretion in parietal cells. Acid secretion is increased by acetylcholine (ACh) and gastrin, which is mediated by M3-receptors and cholecystokinin B (CCKB) receptors, respectively. Stimulation of both receptors increases cytosolic Ca2+ levels. Histamine, released from enterochromaffin-like (ECL) cells, increases acid secretion by activating H2-receptors, which increases cyclic AMP (cAMP) formation. Prostaglandin E decreases acid secretion by activating EP3 receptors, which inhibits cAMP formation. Ca2+ and cAMP activate protein kinases, which translocate H+, K+-ATPase to the apical membrane of the cell to pump H+ into lumen. Also, gastrin and ACh stimulate histamine release from ECL cells by activating CCKB and M1-receptors. AC, adenylyl cyclase; PLC, phospholipase C.
C. Mucosal cytoprotectants
1. Pharmacologic protection of the gastric mucosa can be enhanced by administration of a prostaglandin E1 analog (Misoprostol) or by promoting direct cytoprotection of denuded mucosa (sucralfate).
2. Misoprostol
a. Mechanism of action. Misoprostol has two functions that make it a useful protective agent. It directly inhibits gastric acid secretion by parietal cells and it facilitates PGE-mediated mucosal defenses and healing in response to acid-related injuries.
b. Therapeutic uses. Misoprostol is used to treat gastric ulceration when caused or aggravated by NSAIDs drugs.
c. Pharmacokinetics. Approximately 90% of the drug is readily absorbed from the GI tract where a significant amount is metabolized via a first-pass hepatic effect. The presence of food and antacids will delay drug absorption. Metabolites and small amounts of parent drug are excreted in urine. The duration of action is 3–6 hours.
d. Administration. Misoprostol is given orally three times daily.
e. Adverse effects. Adverse GI signs include diarrhea, vomiting, and abdominal pain. It should not be given to pregnant animals as it will promote uterine contractions.
3. Sucralfate
a. Mechanism of action. Sucralfate is a sucrose sulfate-aluminum hydroxide complex which polymerizes to a viscous gel at pH < 4 and coats ulcer craters. Sulfate groups bind to proteins in ulcerated tissue and protect ulcers from acid and pepsin.
b. Therapeutic uses. Sucralfate provides locally acting treatment for GI ulceration. It also provides cytoprotection when used as a slurry in animals having mucosal disruption of the esophagus (esophagitis).
c. Pharmacokinetics. Only 3–5% of an oral dose of sucralfate is absorbed where it is then excreted in the urine unchanged. The remainder of the drug is converted into sucrose sulfate in the gut by reacting with HCl. The duration of action persists for up to 6 hours after oral dosing.
d. Route of administration. Sucralfate is given orally 2–3 times daily depending on the severity of mucosal disruption.
e. Adverse effects. Sucralfate may impair absorption of other oral medications so it is advised to stagger administration with other drugs by 2 hours or more.
V. PROKINETIC DRUGS
A. General considerations. GI motility disorders result from diseases that, either directly or indirectly, alter normal GI functions (e.g., storage of ingesta, mixing and dispersion of food, and timely propulsion of luminal contents aborally). Briefly, the causes for GI transit disorders are diverse but include both structural (mechanical obstruction) and functional (defective propulsion associated with mucosal inflammation) diseases. Prokinetic drugs act to increase GI motility by stimulating smooth muscle contractions.
B. Specific drugs
1. Cisapride
a. Mechanism of action. Cisapride enhances the release of acetylcholine at the myenteric plexus, but does not induce nicotinic or muscarinic receptor stimulation. Cisapride blocks dopaminergic receptors to a lesser extent than does metoclopramide. This drug is no longer commercially available and must be obtained from a compounding pharmacy.
b. Therapeutic uses. Cisapride stimulates GI motility from the lower esophageal sphincter (LES) to the descending colon. Proposed uses for cisapride in small animals include gastric/intestinal stasis, reflux esophagitis, and constipation/megacolon in cats.
c. Pharmacokinetics. Information only in humans is available: Cisapride is rapidly absorbed following oral administration with an absolute bioavailability of 35– 40%. The drug is highly bound to plasma proteins and is extensively distributed throughout the body. Its elimination t½ is 8–10 hours.
d. Administration. The drug is administered orally at a range of 0.1–0.5 mg/kg PO q8 hours.
e. Adverse effects. The adverse effect profile is ongoing but the primary adverse effects are GI in origin, including diarrhea and abdominal pain.
2. Metoclopramide
a. Metoclopramide stimulates motility of the proximal GI tract, especially the LES and stomach. See Section IX for more detailed information.
b. Metoclopramide exerts its effects through antagonism of dopaminergic D2 receptors and agonism of serotonergic 5-HT4 receptors.
c. Clinically useful in cases of reflux esophagitis and gastric stasis or hypomotility.
3. Ranitidine
a. In addition to its antisecretory activity, ranitidine stimulates GI motility by inhibiting acetylcholinesterase activity. See gastric antisecretory drugs for more detailed information.
b. As a parasympathetic potentiating agent, ranitidine stimulates gastric emptying and small intestinal and colonic motility. Its actions appear to be greatest in stimulating gastric motility.
4. Erythromycin
a. The effect of erythromycin on GI motility most closely mimics that of the GI hormone, motilin. It stimulates motility by means of direct motilin-receptor activation (cats) and indirect cholinergic and neurokinin activation (in dogs).
b. Sub-antimicrobial doses (0.5–1.0 mg/kg) are orally administered to induce prokinetic activity in dogs and cats. GI motility is stimulated most robustly in the proximal GI tract.
c. Erythromycin is used clinically to increase gastric emptying and for the therapy of reflux esophagitis.
VI. DIGESTANTS
A. Pancrelipase (Pancreatin)
1. Pancrelipase consists of pancreatic enzymes, including lipase, amylase, and protease, and is derived from porcine pancreas.
2. Pancrelipase powder preparations are mixed with food to treat exocrine pancreatic insufficiency in dogs and cats.
3. Enteric coated tablets have limited efficacy and are not recommended because of delayed gastric emptying of these preparations.
4. The maintenance dosage for the powdered preparation is 1 tsp/meal for dogs that weigh 20–30 kg.
FIGURE 11-3. Overview of medical therapy for canine and feline hepatopathy. Therapy may be symptomatic and/or specific as dictated by the histopathologic findings obtained through the performance of hepatic biopsy. Note that both dietary and pharmacotherapy are utilized in dogs and cats to reduce hepatic workload, to treat signs of hepatic encephalopathy, and to facilitate repair of injured liver parenchyma.
VII. DRUGS USED FOR TREATMENT OF LIVER DISEASES
A. General considerations. A variety of diverse and clinically useful medications are used to treat dogs and cats with liver diseases. Unfortunately, few controlled clinical trials exist that provide critical evaluation of their effectiveness. Drug therapy is one important arm in treating hepatobiliary diseases along with dietary therapy. Symptomatic and specific therapies for liver disease are diverse but generally include both dietary and pharmacotherapy to induce patient remission (Figure 11-3).
B. Glucocorticoids (Prednisone and Prednisolone) (see Chapter 12 for more information)
1. Steroid therapy is the most commonly used therapy for chronic hepatitis in dogs. Prednisone must be metabolized into prednisolone by the liver so it is best to use prednisolone in case of liver disease.
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