G a s t ro p ro t e c t i v e T h e r a p y

M. Katherine Tolbert, DVM, PhD, DACVIM

KEYWORDS
 Gastric ulcer  Acid suppressant  Proton pump inhibitor
 Histamine-2 receptor antagonist

KEY POINTS
 A range of gastroprotective drugs are available for the treatment of upper gastrointestinal
injury, including acid suppressants, coating agents, prostaglandin analogs, and antacids.
 The choice of gastroprotective drug is guided by the cause and location of gastrointestinal
injury and the potential for adverse effects.
 Proton pump inhibitors are the most effective drugs for the medical treatment of upper
gastrointestinal injury.
 However, proton pump inhibitors are not effective for all causes of upper gastrointestinal
injury and bleeding.

Gastric acid secretion is triggered by hormonal and neural stimulation of parietal cells,
the acid-producing cells of the stomach. The predominant stimulators of acid secre-
tion are gastrin (released from gastric G cells), acetylcholine (released from vagal in-
puts), and histamine (released from enterochromaffin-like cells in the gastric
fundus), whereas the major inhibitors are somatostatin (released from gastric D cells)
and prostaglandins. Gastric acid secretion can be characterized by the phase of acid
secretion and depends on the timing of the meal. Gastric acid secretion is divided into
3 phases: (1) cephalic, in which the sight and smell of food triggers a small amount of
gastric acid secretion; (2) gastric, in which gastric distension and digested food,
particularly proteins, are responsible for the largest amount of gastric acid secretion;
and (3) intestinal, in which gastric acid secretion is inhibited after gastric emptying and
a decrease in duodenal pH. Basal acid secretion occurs during fasting periods,
whereas the highest gastric acid secretion occurs after ingestion of a meal and the
subsequent gastric distension. In dogs and cats, unlike studies in humans, food
seems to be a strong stimulus of acid secretion and no buffering effect of food can
be detected on gastric pH (Fig. 1).
Gastroprotectants are widely used by veterinarians for the treatment of esophagitis
and gastroduodenal mucosal injury or ulceration in dogs and cats. Despite their wide-
spread use, there are only a handful of studies investigating the use of these drugs in

Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M College
of Veterinary, 4474 TAMU j College Station, TX 77843-4474, USA
E-mail address: [email protected]

Vet Clin Small Anim - (2020) -–-

https://doi.org/10.1016/j.cvsm.2020.09.001 vetsmall.theclinics.com
0195-5616/20/ª 2020 Elsevier Inc. All rights reserved.
2 Tolbert

Fig. 1. Gastric pH over time in a healthy dog. Time in hours is on the x-axis and pH is on the
y-axis. The asterisks (*) denote feeding times. Gastric pH is not significantly buffered by
meals.

healthy cats and dogs and even fewer in those with naturally occurring disease. Most
of the guidelines for therapy are derived from those established for humans, but there
can be no certainty that these guidelines are appropriate for small animals. Many of
the drugs are available over the counter and clients are often not provided instructions
for discontinuation, which can result in months to years of inappropriate therapy.
Moreover, this class of drugs is often used for dogs and cats with vomiting, presumed
gastritis, or as preventative therapy for a wide range of diseases with little evidence for
a benefit. Before prescribing gastroprotectants, it is important for the clinician to ask
the following questions: (1) Is there an appropriate indication for the use of the drug?
(2) What objective measures will be used to determine if a beneficial effect is
achieved? (3) Have I provided adequate instructions for use and discontinuation of
the drug? The reader is referred to the American College of Veterinary Internal Medi-
cine consensus statement for more details on the indication and rationale for the use
of gastroprotective therapy in dogs and cats.1 A brief summary of the mechanisms for
and causes of gastroduodenal ulceration as well as a review of drugs used for the
treatment of gastroduodenal ulceration are provided in this article, and the recommen-
ded drug dosages are listed in Box 1.

GASTRODUODENAL ULCERATION IN DOGS AND CATS

Gastroduodenal ulceration results from a breakdown in the mucosal barrier either from
physical disruption of the barrier, altered mucosal blood flow, or utilization of or
decreased local mucus and bicarbonate secretion. Common causes of ulceration in
the dog include nonsteroidal anti-inflammatory drug toxicity and gastroduodenal or
pancreatic neoplasia. Although nonsteroidal anti-inflammatory drug-induced ulcera-
tion can occur in the cat, cats seem to be less susceptible than dogs. Gastroduodenal
or pancreatic neoplasia is the most common cause of ulceration in the cat. Other
 Gastroprotective Therapy 3

Box 1
Gastroprotective drugs

H2 receptor antagonists
 Famotidine: 1 mg/kg q 12 h PO, SC, IV (cat, dog); 8 mg/kg/d IV CRI (dog)
 Ranitidine: 2.0 to 3.5 mg/kg PO*, SC, IV q 12 h
Proton pump inhibitors
 Omeprazole, pantoprazole: 1 mg/kg q 12 h PO, IV, SC
 Esomeprazole: 1 mg/kg q 12 h IV, 1 mg/kg q12 to 24 h PO, SC (dog); 1 mg/kg q12 h IV, PO (cat)
Coating agents
 Sucralfate slurry (tablet crushed and dissolved in water): 0.5 to 1.0 g q 6 to 8 h PO (dog);
0.25 g q 6 to 8 h PO (cat)
 Barium: 1 to 2 mL/kg q 8 to 12 h PO, per rectum (colorectal bleeding)
Prostaglandin analogs
 Misoprostol: 3 mg/kg q 8 to 12 PO (dog)
Abbreviations: CRI, constant rate infusion; IV, intravenously; PO, by mouth; q, every; SC,
subcutaneously.
*See text regarding concerns for oral administration.

causes of ulceration in the cat or dog include advanced liver disease (ie, portal hyper-
tension, intrahepatic portal vein shunting), high-dose corticosteroids, foreign bodies,
trichobezoars inflammatory bowel disease, and severe stress (eg, critical illness,
high-intensity exercise). It is important to note that gastroprotective therapy may not
be effective depending on the underlying cause of ulceration (eg, portal hypertension).

ANTACIDS

Medical treatment of upper gastrointestinal (GI) ulceration can be directed toward

neutralizing gastric acid, promoting prostaglandin production or action, coating and
protecting denuded epithelium, and promoting clot formation and stabilization. Ant-
acids (eg, calcium carbonate, aluminum hydroxide, and magnesium hydroxide)
neutralize local gastric acid, but do not effectively inhibit gastric acid secretion and
are therefore less effective than acid suppressants in treating gastric ulceration. More-
over, they need to be administered frequently to maintain their effect on gastric acid
neutralization, which can be problematic in vomiting dogs and cats. Therefore, ant-
acids are not recommended as a sole therapy for the treatment of gastric ulceration.
Antacids might have a beneficial effect in dogs and cats with painful erosive or ulcer-
ative lesions such as oral mucositis or erosive esophagitis. They can also promote
local prostaglandin production. The side effects of antacid administration include con-
stipation (aluminum preparations), diarrhea (magnesium preparations), and electrolyte
derangements.

COATING AGENTS
Sucralfate
Sucralfate is composed of a polyaluminum sucrose sulfate that is divided into sucrose
sulfate and aluminum salts in the presence of gastric acid. The negatively charged sul-
fate groups protect the ulcerated tissue from additional injury by binding electrostat-
ically to positively charged proteins exposed in ulcerated areas. Sucralfate’s affinity for
abnormal, injured tissue is 5 times greater than for normal mucosa. Sucralfate also de-
creases pepsin activity and stimulates the release of protective prostaglandins, which
4 Tolbert

in turn increases mucosal blood flow and increases mucus production and viscosity.2
Sucralfate is particularly beneficial where pain is an anticipated sequela, such as with
reflux esophagitis. In a canine ex vivo model of acid-induced injury, sucralfate was
effective at restoring gastric barrier defects.3 Based on comparative studies in
humans, sucralfate might be more effective in the adjunctive treatment of duodenal
ulcers compared with gastric ulcers. Importantly, it should be given as a commercially
available suspension (eg, sucralfate [Carafate] suspension) or slurry rather than
crushed or given as a whole tablet. A slurry may be prepared just before administration
by dissolving a 1 g tablet in approximately 10 mL of water and allowing the mixture to
stand for 15 to 20 minutes. The slurry should be shaken well before administration. Fla-
vorings can be added, if needed, to improve palatability. Sucralfate is associated with
very few adverse effects aside from constipation and drug interactions. However, its
use, especially at high doses, is discouraged in cats with chronic kidney disease.4
Sucralfate does change the pH of the stomach and therefore can interfere with the
metabolism of drugs that are dependent on an acidic gastric pH (eg, proton pump in-
hibitors [PPIs]). It also interferes with drugs affected by the aluminum component of
sucralfate (eg, tetracyclines, ciprofloxacin).5,6 Therefore, these drugs (eg, acid sup-
pressants, antibiotics) should be administered at least 2 hours before or after sucral-
fate administration.

Barium
Barium, like sucralfate, is proposed to have mucosal protecting effects and hemostat-
ic properties. However, to the authors’ knowledge, there are no published studies
evaluating the efficacy of barium for gastric injury or bleeding. Barium enemas are
effective for treatment of lower GI bleeding in people but there are no studies evalu-
ating barium enemas in dogs or cats. The dose recommended for mucosal hemosta-
sis (1–2 mL/kg) can be occasionally challenging to administer orally especially in a
patient with a history of dysrexia or vomiting. Although barium is inert, aspiration of
barium with gastric fluid contents can be fatal. Discontinue barium for at least 24 hours
before GI endoscopy and do not use in animals where GI perforation is suspected.

ACID-SUPPRESSING DRUGS
Histamine Type 2 Receptor Antagonists
Gastric acid secretion is triggered by hormonal and neural stimulation of parietal cells,
the acid producing cells of the stomach. Acid-suppressing drugs, which take aim at
these physiologic targets on the parietal cell surface, have largely supplanted antacids
(acid-neutralizing drugs) as the drugs of choice for acid-related diseases. Histamine
type-2 receptor antagonists (H2RAs) were developed in the 1970s after the identifica-
tion of histamine type-2 receptors and proton pumps on parietal cells.7 Gastrin, acetyl-
choline, and histamine were identified as the major secretagogues of gastric acid
secretion with histamine recognized as the most potent secretagogue. Healing of
acid-related disorders was determined to be partially dependent on gastric acid sup-
pression. Thus, H2RAs became the standard of care for the treatment of gastric ulcers
and erosive esophagitis in humans and animals until the development of PPIs in the
1980s.
The H2RAs (eg, famotidine, ranitidine, cimetidine hydrochloride) are competitive in-
hibitors of the interaction of histamine with the histamine type-2 receptor on the pari-
etal cell. They have a good safety profile and can be administered with a full meal.
Cimetidine was the first H2RA to be used clinically in dogs and cats. When adminis-
tered orally 3 times daily, its effect on reducing aspirin-induced gastritis is comparable
 Gastroprotective Therapy 5

to once-daily orally administered omeprazole.8 However, its potency is diminished

compared with famotidine and ranitidine. Unlike the other H2RAs, cimetidine inhibits
cytochrome P450, which can result in drug interactions with other drugs influenced by
the cytochrome P450 system.9,10 Cimetidine may also decrease hepatic blood flow.11
For these reasons, the use of cimetidine for the treatment of erosive and ulcerative dis-
eases in dogs and cats is not recommended. Ranitidine has poor acid suppressant
activity as determined by studies in both healthy cats and dogs in which it was no bet-
ter than placebo in increasing the gastric pH when administered orally or intrave-
nously, respectively, at approximately 2 mg/kg every 12 hours.12,13 Ranitidine is
more commonly used to promote GI motility, although in the majority of studies in
healthy dogs the effects of ranitidine on the prevention of gastroesophageal reflux14
and promotion of gastric emptying15 were largely absent. More studies are needed
to determine if ranitidine has a prokinetic effect in dogs with GI motility disorders.
The presence of the probable human carcinogen, N-nitrosodimethylamine, in several
generic and brand-name ranitidine products may limit the availability of ranitidine for
veterinary practitioners.
Famotidine has good (cats) to excellent (dogs) acid suppressing activity during the
first few days of intravenous or oral administration and has a good safety profile.12,16,17
Intravenously administered famotidine was anecdotally reported to cause hemolysis
in cats; however, this effect has not been documented when the drug is intravenously
administered as a slow bolus over 5 minutes.18 Repeated daily oral administration of
famotidine, and likely the other H2RAs, results in a diminished effect in healthy dogs
and cats,16,17,19,20 which might occur within 2 to 3 days of therapy. In humans, a dimin-
ished effect or tachyphylaxis to the drug occurs regardless of the type of H2RA used,
or dosage or frequency administered, as long as the drug is given daily. Intravenous
administration of famotidine also results in tolerance in humans, but this effect has
not been demonstrated in dogs and cats.
Because of their relatively weak acid-suppressing activity after several days of
use, H2RAs should not supplant PPIs for the treatment of moderate to severe gastro-
duodenal erosion or ulceration especially those which require prolonged treatment
such as ulceration secondary to gastric tumors. Moreover, H2RAs should not be
combined with PPIs for the treatment of ulcerative disease as there is no benefit
to this practice in raising gastric pH.21 H2RAs are a good choice when only weak
acid suppressant activity is needed, for immediate relief of symptoms when taken
on an as needed basis (eg, bilious vomiting), or short-term such as in preventative
therapy for esophageal reflux under anesthesia. The H2RAs are also effective
against basal acid secretion and therefore have efficacy against nocturnal gastric
acidity. Therefore, there might be some benefit in the combination of a PPI with
nighttime famotidine for the treatment of gastroesophageal reflux. When pantopra-
zole shortages dictate the need for H2RA use in dogs with ulcerative disease or
when more aggressive acid suppression is needed, a continuous rate infusion of
famotidine at 8 mg/kg/d has been demonstrated to provide excellent acid suppres-
sion.22 Intravenously administered esomeprazole can also be considered for these
patients.23 Famotidine is renally excreted and should be dose reduced in dogs
and cats with acute kidney injury or chronic kidney disease.

Proton Pump Inhibitors

The PPIs (eg, omeprazole, esomeprazole, pantoprazole) target the final common
pathway of acid production and inhibit gastric secretion regardless of the stimulus.
The PPIs are lipophilic, weakly basic drugs that permeate the parietal cell membrane
and become trapped in its acidic environment. Once trapped, the drug forms disulfide
6 Tolbert

bonds with the active proton-pumping H1-K-ATPase enzymes. The PPIs are more
effective than H2RAs in healing upper GI erosion and ulceration.24 Indeed, a variety
of omeprazole formulations (whole and divided enteric-coated tablet, capsule, refor-
mulated paste, suspension) have been evaluated and demonstrated to be superior
in raising the gastric pH in healthy dogs and cats compared with H2RAs.12,13,19,20
Although peak concentrations of H2RAs occur within hours of oral administration
and the PPIs can take up to 4 days to reach peak effect, PPIs are likely as effective
as H2RAs on day 1 of administration. Orally administered PPIs should be given on
an empty stomach immediately before offering a full meal. A small treat can be given
with the drug if necessary to aid in oral administration.13
Although keeping the enteric-coated tablet intact is desired when possible, the
tablet can be divided to optimize dosing for cats and small dogs. The degree of
acid suppression is likely not as good on day 1 compared with an intact tablet, but pro-
vides good acid suppression over time as any drug that escapes premature gastric
degradation begins to provide its own “enteric coating” by raising the gastric pH.19
For most causes of upper GI ulceration or bleeding, dogs and cats should be treated
twice daily with a PPI.12,13,20 However, once-daily treatment may be effective for
certain causes of gastric injury such as with exercise-induced gastritis.24 Once-daily
omeprazole administration is also effective for reduction of aspirin-induced gastritis,
but was no better than placebo for the treatment of mechanically induced ulceration,
which raises concern for once-daily administration of omeprazole for the treatment of
common causes of ulceration, including gastric tumors and nonsteroidal anti-
inflammatory drugs.8 If once-daily administration of a PPI is necessary or compliance
is a concern, orally administered esomeprazole seems to be an effective option even
when dosed once daily.25
Esomeprazole might also be the preferred treatment for erosive esophagitis based
on studies in people and may provide superior gastric acid suppression when intrave-
nously administered as compared with pantoprazole.23 Esomeprazole, in combination
with cisapride, dosed 12 to 18 hours and 1.0 to 1.5 hours before induction is an effec-
tive treatment for prevention of anesthetic-induced reflux in dogs.26 Acid suppres-
sants should be discontinued after anesthetic recovery. Adverse effects of PPI
administration in dogs and cats can include diarrhea (dogs),12,20 induction of intestinal
dysbiosis,27,28 and hypergastrinemia and drug withdrawal-induced rebound gastric
acid hypersecretion.29 The PPIs are the medical treatment of choice for dogs and
cats with documented nonsteroidal anti-inflammatory drug-induced upper GI
bleeding or injury. However, omeprazole administration might induce intestinal injury
when co-administered with the nonsteroidal anti-inflammatory drug, carprofen, in
healthy dogs.30 Thus, prophylactic omeprazole administration to healthy dogs
receiving nonsteroidal anti-inflammatory drugs is not recommended unless other
risk factors for gastric bleeding are present. Serum gastrin concentrations should
normalize within 7 days after PPI or H2RA cessation.31
The PPIs are inhibitors of the hepatic cytochrome P450 system. Thus, drug interac-
tions with concurrent PPI administration are possible with drugs that are affected by
increased gastric pH or cytochrome P450 inhibition. Omeprazole does not diminish
the antiplatelet effects of clopidogrel in healthy dogs. Over-the-counter omeprazole
suspensions can contain xylitol and should not be used in dogs. Chronic use of
PPIs and H2RAs or prophylactic administration for diseases in which a benefit has
not been demonstrated is discouraged owing to reports of an association with a
wide variety of adverse effects in people following long-term PPI use including chronic
kidney disease, osteoporosis and pathologic fractures, community-acquired pneu-
monia, Clostridium difficile-associated diarrhea, and spontaneous bacterial
 Gastroprotective Therapy 7

peritonitis. However, the quality of evidence for a cause-and-effect relationship be-

tween PPIs and these adverse effects is low.

Prostaglandin Analogs
Prostaglandins play a critical role in the integrity of the GI mucosal barrier including by
stimulating the secretion of bicarbonate-rich mucus, enhancing mucosal blood flow,
and promoting epithelial restitution. The most commonly used prostaglandin agonist
in veterinary medicine is misoprostol, a prostaglandin E1 analog. By simulating endog-
enous eicosanoids, misoprostol may offer many of the protective benefits of prosta-
glandins. However, despite its mechanism of action, misoprostol is predominantly
effective for nonsteroidal anti-inflammatory drug-induced injury32 and has no effect
with steroid-associated ulceration.33 Misoprostol may increase GI and urogenital
smooth muscle contractions leading to side effects of cramping, diarrhea, and
abortions.

SUMMARY

Gastroprotectants are widely used by veterinarians for the treatment of esophagitis

and gastroduodenal mucosal injury in dogs and cats. A range of gastroprotective
drugs are available including acid suppressants (ie, histamine-2 receptor antagonists,
PPIs), coating agents, prostaglandin analogs, and antacids. Of these, the PPIs are the
most effective drugs for the medical treatment of upper GI injury. However, PPIs are
not effective for all causes of upper GI injury and bleeding. The choice of gastropro-
tective drug should be guided by the cause and location of GI injury and the potential
for adverse effects. Detailed instructions for proper use of the medication including
when to discontinue the drug should be provided in all cases.

DISCLOSURE

The author is a consultant for TriviumVet, Inc. Studies performed by the author in the
text above were supported by the Comparative Gastroenterology Society, American
Veterinary Medical Foundation, Winn Feline Foundation (W17-017), Miller Trust
(MT18-004), UTK Companion Animal Fund, and the ACVIM Foundation.

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 Gastroprotective Therapy 9

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