GI Therapeutics
World Small Animal Veterinary Association World Congress Proceedings, 2003
Edward J. Hall, MA, VetMB, PhD, DECVIM-CA, MRCVS
University of Bristol, Dept. Clinical Veterinary Science, Langford House
Langford, Bristol, England

Anti-emetics

The phenothiazines (e.g., chlorpromazine) and antihistamines (e.g., diphenhydramine) remain effective anti-emetics in the right situation, but tend to cause drowsiness.

Metoclopramide

Metoclopramide (Reglan), a well recognised and generally safe anti-emetic and prokinetic, is thus the first choice in dogs. Although it has no direct effect on gastro-oesophageal healing, it helps by increasing lower oesophageal tone and emptying the stomach of toxic acid, pepsin and bile salts. It has a central anti-D2 dopaminergic effect, being active against centrally-acting emetics. It also has a peripheral cholinergic effect stimulating upper GI motility, and is contra-indicated in GI obstruction. In some patients, especially cats, it may cause bizarre behavioural changes. Excreted by the kidneys, toxicity is more likely with renal insufficiency. Continuous IV infusion is useful in dogs recovering from Parvovirus.

Ondansetron

Ondansetron (Zofran) is a 5-HT3 antagonist and a very potent anti-emetic but is very expensive. Side-effects are mild. Related drugs (e.g., granisetron) are available.

Prokinetics

Metoclopramide & ranitidine

Their prokinetic activities are discussed elsewhere.

Cisapride

Cisapride was the most effective prokinetic but has now been withdrawn in many countries because of fatal arrhythmias in humans. Newer, related agents, prucalopride and tegaserod, are being developed and will hopefully take its place. Cisapride acted by stimulating intestinal 5HT4 receptors:

 increased LES tone

 decreased pyloric tone

 propulsive peristaltic waves from stomach to colon It is indicated for gastro-oesophageal reflux and GI motility disorders including feline idiopathic megacolon.

Erythromycin

The emetic effect of antibacterial doses (10 mg/kg) of erythromycin is well recognised. It is caused by stimulation of motilin receptors in the GI tract. At lower doses, erythromycin stimulation causes more normal migrating motor complexes. Thus, at doses of 1-2 mg/kg q 8h, it can be used as an effective prokinetic.

Acid blockers

H2 antagonists

Cimetidine (Tagamet) has been in use since the 1970's; it is an effective H2 antagonist that can be given orally or parenterally, but needs to be given at least three times daily. It has significant drug interactions through hepatic cytochrome P450 activity. Ranitidine (Zantac), nizatidine (Axid), and famotidine (Pepcid) are more potent and need to be given only twice or even once daily. Increased potency compared with cimetidine (ranitidine & nizatidine 5x, famotidine 20-30x) is not an advantage if equipotent dosages are used. The advantage of once daily dosing is offset by cost. Ranitidine and nizatidine are also prokinetic, and can be used in gastroparesis and feline idiopathic megacolon. This effect is probably another reason to choose ranitidine over cimetidine to treat non-specific gastritis, in addition to its preferable pharmacokinetic profile.

Proton pump inhibitors (PPi's)

These drugs irreversibly bind the proton pump, and so are very potent inhibitors of acid secretion. They can cause reflex hypergastrinaemia, and induce carcinoid tumours in rodents. A similar sequel has not been seen in dogs, even after many years of use. Once daily administration and only marginally greater cost mean they are being used more often. PPi's are indicated for severe reflux oesophagitis, gastritis and gastric ulcers, and gastrinoma. Omeprazole [Losec (Prilosec in USA)] was the first PPi to be marketed, and is probably the only one needed in companion animal practice. It is available in convenient 10 and 20 mg capsules and an IV preparation.

Mucosal protectants

Sucralfate (Antepsin, Carafate) is a complex of sucrose octasulphate and aluminium hydroxide, available as tablets and suspension. It is believed, simplistically, to aid healing of gastro-oesophageal erosion/ulceration by precipitating and binding to the tissue, providing a barrier against the penetration of gastric acid and pepsin. The safety of sucralfate is well established, but there is debate about its drug interactions. There is a theoretical argument that co-administration of sucralfate with acid blockers (unless given IV) prevents their absorption; conversely the blockade of acid secretion could prevent the binding of sucralfate. These arguments appear to have little basis in fact, and co-administration is probably not a problem. Nevertheless most recommend these drugs are given at least an hour apart, although which should be given first is not clear!

Immunosuppressive agents

Immunosuppression is used to treat idiopathic inflammatory bowel disease (IBD)

Corticosteroids

Prednisolone (and methylprednisolone) remain(s) the first choice immunosuppressive agent in dogs and cats. Equipotent doses of dexamethasone have similar immunosuppressive effects, but have more deleterious effects on brush border enzyme activity and so dexamethasone is not recommended.

Novel steroids

Prednisolone suppression of the HPA axis and the consequent side-effects have led to attempts to find safer steroids. Budesonide has been given to dogs and cats with IBD with some success. The correct dose is unknown, but an empirical dose of 3 mg q12h in dogs and 1 mg q12h in cats has been suggested for the inhalant product (Rhinocort). An enteric-coated formulation in 3 mg capsules (Entocort CR, Budenofalk) is now available. The dose and value of this preparation in animals is unclear. Furthermore, steroid hepatopathy still seems to be a problem in dogs.

Azathioprine

This is an effective immunosuppressive agent (Imuran, 2 mg/kg/day in dogs). Its major use is as a steroid-sparing drug in patients suffering iatrogenic Cushing's. Bone marrow toxicity is uncommon in dogs, but will occur quite rapidly (1-2 weeks) in some individuals. They probably lack an enzyme (thiopurine methyltransferase, TPMT) necessary to degrade its active metabolite, 6-mercaptopurine. This enzyme is low in about 10% of dogs but in almost 100% of cats. This explains why the safety of azathioprine in cats has been questioned and why the dose (0.3 mg/kg/day) is so much lower than in dogs. It is not a good choice for feline IBD, and other agents, such as chlorambucil (2 mg/cat every 4-5 days) or cyclophosphamide, are better choices if prednisolone alone is not effective.

Cyclosporine

This anti-rejection drug is beginning to find uses in veterinary medicine to treat immune-mediated diseases. Preliminary studies in idiopathic canine IBD have shown variable success.

Anti-inflammatory drugs

In general, non-steroidal anti-inflammatory drugs (NSAIDs) are toxic to the gastric mucosal barrier, and may damage the SI. In addition, intestinal absorption predisposes to renal toxicity, particularly in dehydrated, diarrheic patients. However, systems that deliver NSAIDs to the colon are useful in treating colitis.

5-Aminosalicylic acid (5-ASA) derivatives

Sulphasalazine (Azulfidine, Salazopyrin) is indicated for the treatment of idiopathic colitis. Within the drug, a diazo bond (binding a sulpha- moiety to 5-ASA) is cleaved by colonic bacteria. This releases free 5-ASA, which acts locally in high concentrations as an anti-inflammatory. Unfortunately a major side-effect, keratoconjunctivitis sicca, is well recognised. Sulphasalazine may inhibit TMPT activity, and myelosuppression is a greater risk if it is used concurrently with azathioprine.

Olsalazine (Dipentum) is two 5-ASA moieties again released by colonic bacteria. It has been used successfully in dogs, although KCS has still been reported, and the dose is one half the dose of sulphasalazine.

A new derivative, balsalazide (Colazide) is also pro-drug (4-aminobenzoyl-β-alanine-5-ASA) releasing free 5-ASA, but has not been tried in animals. Slow-release enteric formulations of 5-ASA (mesalazine, Pentasa) are available but premature release may cause absorption and nephrotoxicity in dogs and cats.

Anti-TNFa drugs

TNFα is considered to be one of the lynch pins in the intestinal inflammatory cascade. It can be inhibited by corticosteroids, pentoxifylline, thalidomide, and monoclonal antibody (Infliximab, Remicade)

Probiotics

Probiotics are live micro-organisms, administered orally, that alter the intestinal microflora with a beneficial effect on intestinal health. Possible mechanisms for probiotic activity include:

 production of antimicrobial metabolites

 competitive interactions (receptor binding)

 interaction with epithelial function

 immune modulation Probiotics may become a simple adjunct to conventional treatment of intestinal disease in dogs and cats as soon we can give the appropriate strain(s) at the right dose and at the right time. Until then, the empirical administration of live yoghurt is likely to be of little benefit.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Edward J. Hall, MA, VetMB, PhD, DECVIM-CA, MRCVS
University of Bristol, Dept. Clinical Veterinary Science
Langford, Bristol, England


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