Download drug treatment of gastric diseases of dogs and cats

DRUG TREATMENT OF GI DISEASES OF DOGS AND CATS
Michael S. Leib DVM, MS, Diplomate ACVIM
Virginia Maryland Regional College of Veterinary Medicine, Blacksburg, VA
Many drugs are available to treat the clinical signs associated with GI diseases or to treat
the disease process itself. A though knowledge of these drugs, including several of the newer
developments, is necessary for the practitioner to effectively treat dogs and cats with GI diseases.
ANTIEMETICS
Antiemetics are effective in reducing the frequency of vomiting or in some cases
completely eliminating it. In the outpatient it relieves a very objectionable clinical sign for the
owner. In the hospitalized patient it reduces the severity of dehydration and electrolyte changes
and allows the animal to rest. Antiemetics should be used cautiously, as continued vomiting is an
important sign that the underlying condition may be progressing or that an incorrect diagnosis has
been made. Masking this important parameter may give the clinician a false sense of security that
the animal is improving, when actually heightened surveillance and therapy is indicated. The
author is most comfortable prescribing antiemetics when a definitive diagnosis has been reached
or when used for only a brief period in animals with self-limiting vomiting.
Phenothiazines
Phenothiazines are potent centrally acting drugs that block both the vomiting center and
the CRTZ. They are dopamine antagonists with antihistaminic and weak anticholinergic properties.
They can not be administered until the animal has been rehydrated because they are alphaadrenergic receptor blockers and can cause hypotension. Even at low doses they produce
tranquilization, which has the benefit of promoting rest and reducing stress, but the disadvantage
of interfering with monitoring the animal's attitude. They should not be used in animals with
epilepsy as they may lower the seizure threshold. They can be given IM or SQ and several are
available in suppository form. Recommended dosages of commonly used drugs include
chlorpromazine (Thorazine) 0.2-0.5 mg/kg TID to QID and prochlorperazine (Compazine) 0.5
mg/kg TID to QID.
Metoclopramide
Metoclopramide (Reglan) is a highly effective antiemetic with both central and peripheral
effects. Metoclopramide is a dopamine antagonist that very effectively blocks the CRTZ and
raises the threshold of the vomiting center. Peripherally it augments acetycholine release from
postganglionic nerves and increases the tone and amplitude of gastric contractions and increases
gastroesophageal sphincter pressure. These actions oppose some of the physical events
necessary for the vomiting reflex to occur. Short term side effects are uncommon and include
depression, nervousness, and restlessness. Metoclopramide is contraindicated in intestinal
obstructions. Dosages of 0.2-0.4 mg/kg TID SQ are often effective. Because it has a short half
life it may need to be administered by constant infusion 1.0-2.0 mg/kg/day IV.
Metoclopramide can also be used to treat esophagitis. Increasing tone of the GES helps
to reduce the reflux of acid which would impede healing of the esophageal mucosa. Increasing
gastric motility and emptying will help to move acid and ingesta out of the stomach into the
duodenum, reducing the amount available to reflux into the esophagus. Metoclopramide's
prokinetic effects are useful in treating gastric motility disorders, a group of under diagnosed
conditions causing chronic vomiting (see article on gastric motility disorders.
Ondansetron
Ondansetron (Zofran) is a serotonergic antagonist that is very effective in blocking the
nausea and vomiting associated with chemotherapy. It is effective in blocking neural
transmission in both the chemoreceptor trigger zone and in vagal afferent pathways. Dosages of
0.5-1.0 mg/kg PO can be given 30 minutes prior to administration of chemotherapy. It can also be
used to reduce vomiting associated with GI disorders at 0.1-0.15 mg/kg slow IV BID-QID. The
author has not found it necessary to use the drug in this manner, although others have found it
very effective. Presently, the drug is very expensive.
Maropitant – Cerenia TM
Maropitant is a neurokinin receptor antagonist that blocks the actions of substance P in
the central nervous system. It was recently released in the summer of 2007. It is approved for
the prevention and or treatment of acute vomiting and motion sickness in dogs > 16 weeks of
age. Dosage for motion sickness is 8 mg/kg PO q 24H. Dosage for acute vomiting is 1 mg/kg
SC q 24 H for up to 5 days. The drug is metabolized via hepatic P450 enzymes. Safe drug and
side effects are similar to placebo. It was more effective than metoclopramide in a European
clinical study in reducing vomiting in a large number of dogs with a variety of common causes for
acute vomiting. It has also been shown to reduce vomiting associated with cisplatin
administration in dogs with neoplasia.
EROSION AND ULCER THERAPY
Erosion and ulceration of the gastric and duodenal mucosa commonly occur in chronic
gastritis and gastric-duodenal ulcer disease. Back-diffusion of acid across a damaged mucosa
leads to further damage and retards healing processes. Reduction of gastric acid secretion,
protection of ulcerated mucosa, or augmentation of cytoprotection promotes healing of erosions
and ulcers.
H-2 Receptor Blockade
Drugs such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepsid), and
nizatidine (Axid) block the H-2 receptor on the gastric parietal cell and dramatically decrease acid
production. Cimetidine (5-10 mg/kg QID) and ranitidine (2 mg/kg BID-TID) have been used most
commonly in veterinary medicine. Both can be given orally or parenterally and have not been
commonly associated with adverse effects. Cimetidine can inhibit hepatic cytochrome P-450
enzymes, potentially interfering with the metabolism of other drugs. Famotidine, 0.5 mg/kg SIDBID, and nizatidine, 5 mg/kg SID (this dosage has not been well established), have not been
used as frequently in veterinary medicine, but are also effective. All four of these drugs are now
available over the counter in smaller dosage forms than prescription strength, making treatment
of cats and small dogs easier. Elixirs are available for cimetidine, ranitidine, and famotidine.
Sucralfate
Sucralfate (Carafate) is a sulfated disaccharide that forms an adherent gel and binds to an
ulcer crater, protecting it from acid and pepsin. It also stimulates the synthesis of prostaglandin,
increases mucosal cytoprotection, and binds epithelial growth factor at the ulcer, where it
stimulates cellular proliferation. It has been shown to be as effective as H-2 receptor blockers in
healing ulcers in humans. Because sucralfate can bind other drugs, medications should be given
1-2 hours prior to sucralfate administration. The recommended dose is 1 gm/25 kg TID-QID in
dogs and 0.25 gm TID in cats. Because absorption is minimal, toxicity is uncommon. Long-term
use may lead to constipation because of its aluminum content. There is no evidence to support
that combination therapy with an H-2 receptor antagonist provides added benefit compared to
therapy with either sucralfate or an H-2 blocker alone.
Sucralfate is also effective to treat esophagitis because of its ability to coat ulcerated
mucosa. The suspension form is necessary for this indication.
Misoprostol
Misoprostol (Cytotec) is a synthetic prostaglandin that prevents or heals ulcers associated
with NSAID administration by directly increasing mucosal cytoprotection. The suggested dose is
3µg/kg TID. The most common side effect is diarrhea although it can also cause abortion. Its
major indication is preventing GI mucosal injury in dogs with arthritis that require long-term NSAID
therapy. It can also be used to treat cases of GDUD caused by NSAIDS.
Proton Pump Inhibitors (PPI’s)
PPI’s inhibit the action of the proton pump at the apical portion of the parietal cell that
exchanges H+ for luminal K+, thus preventing secretion of acid. As a weak base they accumulate
in the acid compartment of the parietal cell, necessitating only SID administration. Omeprazole
(Prilosec) is the most commonly used PPI in veterinary medicine. The recommended dose is 1.0
mg/kg SID. The enteric-coated granules (20 mg) are packaged in gelatin capsules to resist
degradation by gastric acid. If less than one capsule is to be administered (20 mg), the granules
should be repackaged in gelatin capsules. Zegerid is an omeprazole powder that is mixed with
bicarbonate to protect the drug from gastric acid. It can be divided into smaller doses. Another
PPI, lansoprazole (Prevacid) granules can be mixed in an acid juice, such as apple juice and
administered. Other PPI’s such as pantoprazole (Protonix), rabeprazole (Aciphex),
esomeprazole (Nexium) must be reformulated into a form that protects the drug from gastric acid
damage. Omeprazole also inhibits hepatic p-450 enzymes. Several recent studies have shown
that PPI’s in dogs are better at inhibiting acid secretion than H2 blockers. In humans H2 blockers
begin to suppress acid faster than PPI’s. Also in humans, PPI’s result in faster ulcer healing and
relieve clinical signs sooner than H2 blockers. These effects are not proven in dogs or cats.
HELICOBACTER
Many treatments have been shown to be effective in humans with Helicobacter infection. Little is
known regarding effective treatments in dogs and cats. See The Role of Helicobacter
proceedings for additional information. My currently recommended therapy is three weeks of
omeprazole 0.7 mg/kg SID, amoxicillin 15 mg/kg BID, and clarithromycin 7.5 mg/kg BID.
ACUTE DIARRHEA
Opioids prolong intestinal transport, allowing increased fluid absorption, and decreasing
the frequency and severity of diarrhea. They should not be used if toxins or pathogenic bacteria
are suspected to be the cause of diarrhea. Opioids increase colonic segmentation, reduce
propulsive peristalsis, and increase fluid absorption, decrease intestinal secretion, and increase
anal tone. Loperamide 0.1-0.2 mg/kg q 6-12H or diphenoxylate 0.05-0.5 mg/kg q 6-12 H are very
effective in reducing the frequency and severity of diarrhea. Both are available as elixirs.
Loperamide is more potent and has a faster onset and longer duration of action. Loperamide
does not cross the normal blood brain barrier. However, neurologic toxicity has been seen in
herding dogs with MDR1 mutation. Both can be safely utilized in cats.
INFLAMMATORY BOWEL DISEASE
Prednisone / prednisolone
Corticosteroids are the drugs of choice for cats with colitis and dogs and cats with
enteritis that have failed to respond to dietary management. They are used less frequently in
dogs with colitis as most cases can be managed with sulfasalazine or newer mesalamine
products. In dogs showing adverse effects associated with sulfasalazine, adding corticosteroids
may allow reduction of the sulfasalazine dose.
The efficacy of corticosteroids is thought to be due to their anti-inflammatory, antiprostaglandin, anti-leukotriene, and immunosuppressive effects. They inhibit cell membrane
phospholipase A, suppressing production of arachidonic acid and subsequently prostaglandin
and leukotriene synthesis. Corticosteroids also increase sodium and water absorption and help
regulate colonic electrolyte transport.
An initial dose of prednisone or prednisolone of 2 mg/kg/day often will improve clinical
signs within 7-10 days. Because of reduced metabolism in cats, prednisolone is utilized instead
of prednisone. After vomiting has ceased and normal feces have been produced for 2-4 weeks,
the dosage should be reduced by 25%. As long as clinical signs do not return, the dosage can
gradually be reduced at 2-4 week intervals until the least amount given every other day that
controls clinical signs is reached. Dietary management and/or combination drug therapy can
have a corticosteroid sparing effect.
Adverse effects in cats are uncommon. Side effects are common in dogs and are usually
dose related. Side effects include polyuria-polydipsia, polyphagia, iatrogenic
hyperadrenalcorticism, pituitary-adrenal suppression, gastrointestinal bleeding, acute pancreatitis,
steroid hepatopathy, and predisposition to bacterial or fungal infections.
Budesonide
Can be used when corticosteroid side effects are present although clinical signs have
improved with prednisone. Budesonide is a corticosteroid related to 16- α -hydroxyprednisolone.
Rapid hepatic metabolism (90% first pass) to compounds with minimal biologic activity occur. It
has strong affinity for corticosteroid receptors within GI mucosa. It is formulated in 3 mg coated
capsule that dissolve at Ph>5.5 and deliver medication to distal ileum and proximal colon. Less
systemic effects than prednisone but does suppress the pituitary adrenal axis in dogs. Dosage is
empirical, but 1-3 mg/day has been suggested. Anecdotal evidence supports its efficacy in IBD.
Sulfasalazine
The treatment of choice for dogs with colitis that do not respond to dietary management
is sulfasalazine. Sulfasalazine consists of mesalamine (previously called 5-aminosalicylic acid)
linked by an azo bond to sulfapyridine. This linkage prevents absorption by the small intestine
and allows delivery of approximately 70% of the drug to the colon. Bacteria of the distal small
intestine and the colon break the azo bond liberating both components. Sulfapyridine is
absorbed, metabolized in the liver, and excreted by the kidney. It is not thought to have
therapeutic effects in IBD and may be responsible for the adverse reactions associated with
sulfasalazine. Mesalamine acts topically in the colon to reduce mucosal inflammation. Although
the mechanism of action was once believed to be due to antiprostaglandin activity, recent
evidence supports is antileukotriene activity .
The broad range of actions associated with sulfasalazine are likely responsible for
beneficial effects in IBD. Evidence in human beings and several laboratory species suggests that
in addition to antileukotriene activity, mesalamine inhibits neutrophil chemotaxis, macrophage
chemotaxis and phagocytosis, cell-mediated cytotoxicity, several aspects of platelet function,
mucosal mast cell histamine release, natural killer cell activity, and antibody secretion. It also
decreases production of interleukin-1, tumor necrosis factor and antibodies, and is a reactive
oxygen metabolite scavenger.
The recommended dosage range for sulfasalazine in dogs is 20-50 mg/kg to a maximum
of 1.0 g q8h . High dosages may be needed in chronic cases. When initially treating a dog, a
dosage of 20-30 mg/kg q8h usually is effective. One of the most common therapeutic mistakes is
discontinuation of therapy too soon after resolution of clinical signs, which can lead to diarrhea
that may be refractory to the dosage that previously controlled clinical signs. After a dog has
normal feces for 2-4 weeks the dosing frequency should be reduced to q12h. After an additional
2-4 weeks without diarrhea, maintenance dosages should be decreased by 50%, still given q12h.
If diarrhea returns, the dosage should be increased to the amount that previously controlled
clinical signs. In some dogs, sulfasalazine can be discontinued while other cases require longterm therapy. Concurrent dietary management with a hypoallergenic or a highly digestible diet
may control clinical signs with a lower dosage of sulfasalazine.
Many side effects have been documented in human beings and are believed to be
associated with sulfapyridine. However in dogs, only vomiting and keratoconjunctivitis sicca are
common. Vomiting can usually be controlled by administering medication with food, or using an
enteric-coated preparation. If decreased tear production is detected early, reducing the dosage or
discontinuing the drug may result in increased tear production and prevent progression to
keratoconjunctivitis sicca. However, if decreased tear production is not detected early, it can
become irreversible. The mean duration of treatment with sulfasalazine (approximate dosage
range of 8-90 mg/kg q 8-24h) at the time of diagnosis of keratoconjunctivitis sicca in two studies
was 6-8 months with a range of one month to two years. The mechanism of action for toxicity is
unknown, but sulfapyridine may directly damage the lacrimal and nictitans tear glands, reducing
production of the aqueous component of tears. When initiating sulfasalazine treatment, tear
production should be measured at two-week intervals. If therapy is continued long term, tear
production should be measured monthly. If decreased tear production is detected, the dosage
should be immediately reduced or the drug discontinued and the dog's eyes closely monitored.
Treatment of keratoconjunctivitis sicca associated with sulfasalazine administration with
cyclosporine was shown, in a limited number of cases, to be less successful compared to other
causes.
Sulfasalazine should be used with caution in cats because of their sensitivity to
salicylates. Prednisone is the drug of choice for cats with colitis that fail to respond to dietary
management. Sulfasalazine has been used in cats at 10-20 mg/kg q12-24h. Side effects include
anorexia and anemia. The oral suspension (50 mg/ml) allows accurate measurement of doses
for cats.
Mesalamine
In order to reduce the toxicity associated with sulfasalazine, drugs have been developed
that deliver mesalamine to the colon without linkage to sulfapyridine. These drugs have been
shown to be safe and effective in treating human beings with IBD. Olsalazine, Dipentum®
consists of two molecules of mesalamine linked with an azo bond. Asacol ®consists of
mesalamine coated with an acrylic resin that dissolves at pH 7 or greater, usually in the terminal
ileum and colon. The dosages of Dipentum ® and Asacol® in human beings are 500 mg q12h
and 800 mg q8h respectively. Although there are no firm guidelines for using these drugs in dogs
with colitis, some authors have suggested, 10-20 mg/kg q8h.
Balsalazide (Colazide®) links mesalamine to an inert carrier, 4-aminobenzoyl-B-alanine.
Other delayed release acrylate-coated mesalamine preparations include Claversal® and
Salofalk®. A different type of formulation, Pentasa® utilizes a bead of mesalamine encapsulated
with ethylcellulose, a semipermeable membrane. The drug is slowly released, contingent on the
rate of water absorption and the pH dependent solubility of the encapsulated mesalamine .
These newer agents are less toxic than sulfasalazine as approximately 80-90% of human
beings with sulfasalazine intolerance can be treated with these drugs without adverse effects.
The most common adverse effect of olsalazine in people is watery diarrhea, which may be
minimized by taking the drug with food and gradually increasing the dose.
Although these new drugs have not been used extensively in dogs, keratoconjunctivitis
sicca has unfortunately been associated with Asacol® in a limited number of cases. The
mechanism of toxicity is unknown. Dipentum® and Asacol® should not be the initial drug
treatment in dogs with colitis, but should to be reserved for patients that develop side effects
associated with sulfasalazine.
Metronidazole
Metronidazole possesses several properties potentially beneficial in IBD. Besides
antiprotozoal effects, it is a broad spectrum antibiotic with impressive activity against anaerobic
bacteria, it inhibits cell mediated immunity, alters neutrophil chemotaxis, and may have other
immunosuppressive effects. It can be utilized as a single drug for IBD therapy or along with other
medications to allow dosage reduction of prednisone or sulfasalazine. It can also be utilized for
2-3 weeks during flare-ups of clinical signs in otherwise well controlled animals. 10-20 mg/kg q
12-24H is a typical dose range. Adverse effects are uncommon, but neurologic toxicity can
occur.
Azathioprine
Corticosteroid sparing effects. It is a prodrug for 6-mercaptopurine, which is a purine
analog. It is incorporated into ribonucleotides producing nonfunctional nucleic acid strands and
suppresses several steps in synthesis of adenine and guanine. An antiproliferative effect on
mitotically active lymphocyte populations, reduces the amount of antibody produced. May
possess direct anti-inflammatory properties and inhibit cytotoxic T-cell and NK cell function. Its
metabolite, 6-methylmercaptopurine, may be responsible for hepatotoxicity. Other toxicity
includes bone marrow suppression, vomiting, diarrhea, anorexia, and perhaps pancreatitis.
Starting dosage in dogs 2 mg/kg/day but in cats 0.3mg/kg q 48H is utilized due to bone marrow
suppression.
Cyclosporine
Diminishes cytokine production and exerts and antiproliferative effect on T-lymphocytes.
It prevents production of IL-2, IFN-gamma, TNF-alpha, granulocyte-macrophage colony
stimulating factor, and IL-4. It is metabolized in the liver via P450 enzymes. Drugs such as
ketoconazole, that inhibit hepatic cytochrome P450, increase blood levels of cyclosporine.
Toxicity in dogs includes vomiting, diarrhea, anorexia, gingival hyperplasia, papillomatosis,
hypertrichosis, alopecia and excessive shedding. Seizures may develop in cats. Dosageis
5mg/kg/day. Blood levels can be monitored. It has been shown to be effective in dogs with IBD
that were nonresponsive to prednisone. Pharacokinetics in dogs with IBD have been shown to
be similar to healthy dogs.
IRRITABLE BOWEL SYNDROME
Pain can often be relieved by antispasmotic agents and the effects of stressors can be
reduced by sedatives. Librax® (Roche) contains the sedative chlordiazepoxide (5 mg) and
clidinium bromide (2.5 mg), an anticholinergic agent. A suggested dosage is 0.1-0.25 mg/kg of
clidinium or 1-2 capsules PO BID-TID. The drug can be given when the owner first notices
abdominal pain or diarrhea or when stressful conditions are encountered, and can usually be
discontinued after a few days. Other anticholinergics such as propantheline (Pro-Banthine®,
Searle), 0.25 mg/kg PO BID-TID, hyoscyamine (Levsin®, Schwarz Pharma Kremers Urban),
0.003-0.006 mg/kg PO BID-TID, or dicyclomine (Bentyl®, Lakeside Pharmaceuticals), 0.15 mg/kg
PO BID-TID have been suggested. Anticholinergics can decrease or inhibit GI motility, which
may worsen diarrhea. In people, side effects include xerostomia, urinary retention, blurred vision,
headache, psychosis, nervousness, and drowsiness.
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