Structure and Mode of Action

Histamine 2 receptor antagonists (H2-RA) were the first class of drugs developed to inhibit gastric acid production. H2-RA include cimetidine, ranitidine, and famotidine. The H2-RA bind to and antagonize H2-receptors on gastric parietal cells.^1,2 Binding to the H2-RA prevents histamine-induced increases in intracellular cAMP necessary for the mobilization of the H⁺/K⁺-ATPase proton pump to the apical membrane of the parietal cell. The result is a reduction in parietal cell acid secretion. The H2-RA also inhibit gastrin-induced gastric acid production, because the majority of gastrin-induced gastric acid secretion is not mediated by direct binding of gastrin to the parietal cell but rather by the action of histamine release stimulated after gastrin binding to receptors on enterochromaffin-like cells.²

Pharmacokinetics

The pharmacokinetics of H2-RA administration in dogs has been described.³ Cimetidine, ranitidine, and famotidine are all well absorbed orally with a bioavailability of 70–75% when given on an empty stomach. Peak plasma concentration is reached within 30 min for cimetidine and ranitidine and within 2 hr for famotidine. There is evidence that peak concentration may be delayed or decreased if cimetidine is given with food. Cimetidine half-life is very short (1.6 hr), which explains the need for administration every 8 hr. Famotidine and ranitidine have longer half-lives.^4,5

In humans, elimination of cimetidine, ranitidine, and famotidine involves a combination of hepatic metabolism, glomerular filtration, and tubular excretion.^2,4,6 Oral cimetidine is eliminated 50% by hepatic metabolism via hydroxylation and conjugation and 50% by renal excretion.⁷ Cimetidine is a potent inhibitor of cytochrome P450 function, which can impact the hepatic metabolism of other drugs and lead to important drug interactions (see drug interactions below).² Ranitidine is eliminated mostly (70%) by urinary excretion through a combination of glomerular filtration and tubular secretion.^5,8 Ranitidine is only a weak inhibitor of P450 enzymes and thus is less prone to drug interactions.^2,9 Famotidine is metabolized by the liver and is also eliminated unchanged in the urine.⁶ Very little interaction with cytochrome P450 is reported with famotidine.² Similar detailed information is not currently available in small animals.

Side Effects

Very few adverse reactions have been reported with H2-RA.^2,9–11 Cardiovascular events such as sinus bradycardia, hypotension, or atrioventricular block have been described in humans, especially when the drugs are given as a rapid bolus IV.^9,12 Patients who experience these side effects often have underlying cardiac disease. Still, H2-RA are considered safe drugs relative to the cardiovascular system in humans, and currently there is no data suggesting that they are contraindicated in dogs and cats with heart disease.^12,13

In cats, famotidine has been anecdotally reported to cause hemolytic anemia after IV administration, but this finding was not confirmed in a recent retrospective study.¹⁴ The study did find that cats receiving famotidine had a median packed cell volume significantly lower than cats that did not receive famotidine. It is hard to interpret this finding in light of the retrospective nature of the study, which precluded randomization of cases. In the study, cats receiving famotidine were significantly sicker and received significantly more fluids than control cats. A case report of cimetidine-induced exfoliative dermatitis similar to pemphigus foliaceus has been reported in a cat.¹⁵

Other sides effects H2-RA in humans include gastrointestinal side effects, headache, dry mouth, confusion, delirium (particularly in the elderly), and liver toxicity marked by liver enzyme elevations (rarely hyperbilirubinemia). Blood dyscrasias (such as thrombocytopenia, agranulocytosis, neutropenia, or pancytopenia) have been associated with cimetidine but not ranitidine or famotidine.^1,6 There is also evidence in the human medicine that H2-RA use may increase the risk of acquiring pneumonia or Clostridium difficile infection, but these associations have not been reported in veterinary medicine.^16–19

Drug Interactions

In humans, drug interactions with H2-RA occur due to their ability to either increase gastric pH or inhibit cytochrome P450 enzymes.⁷ Drugs that decrease gastric acid production could theoretically reduce the absorption of weak bases such as ketoconazole and tetracyclines and increase the dissolution and absorption of some weak acids such as acetylsalicylic acid and furosemide. Cimetidine, through the inhibition of the CYP450 enzymes, can increase plasma levels of multiple drugs, including theophylline, warfarin, metronidazole, imipramine, diazepam, phenytoin, lidocaine, quinidine, and propranolol. In dogs, cimetidine has been shown to decrease metabolism of nifedipine, theophylline, and verapamil and to decrease oral clearance of diltiazem, but it does not alter cyclosporine pharmacokinetics.^20–23 Similar information has not been reported in cats.

Structure and Mode of Action

The first commercially available drug that inhibited the apical H⁺/K⁺-ATPase pump on the parietal cell was omeprazole^a. This was soon followed by numerous related compounds including esomeprazole, pantoprazole, lansoprazole and rabeprazole.^24,25 Omeprazole and other proton pump inhibitors (PPIs) are weak bases and they are also considered pro-drugs because they require metabolism into an active form.^24,26,27 This essential step is pH-dependent and occurs within the parietal cell after absorption of the PPI from the duodenum. Once the PPI is activated intracellularly, it binds to and inhibits active H⁺/K⁺-ATPase pumps that are exposed on the cell membrane by forming disulfide bonds with cysteine residues.

Pharmacokinetics

Since all of the PPIs are weak bases, oral formulations need to be protected from degradation by stomach acid so that they can pass into the small intestine where they can be absorbed. Three strategies are used to overcome the instability of PPIs in the acid environment of the stomach (Table 1). The first is to enteric-coat the drug so that it is insoluble in stomach acid but soluble in the neutral or alkaline milieu of the small intestine. The currently available forms include an enteric coated tablet, a capsule containing multiple enteric coated pellets, and an orally disintegrating tablet containing enteric coated microgranules. All of these forms are considered delayed-release forms.^6,28 Some capsules contain a limited number of enteric coated microgranules that allow exact measurement of the PPI dose in each granule.²⁸ However, most of the commercially available capsules contain a large number of granules, which impairs the determination of the exact amount of drug in each granule (Figure 1). A second strategy to protect the PPI from the acidic environment is to mix it with a sufficient amount of substances (e.g., sodium bicarbonate) that will buffer the pH of the stomach contents to a neutral or alkaline pH during the absorption phase. This form is considered an immediate-release because the PPI is not enteric coated (Table 1).^6,29,30 The last strategy is to have the PPI formulated to dissolve and be absorbed rapidly to minimize the time the drug is in contact with stomach acid.

TABLE 1 Formulations of Proton-Pump Inhibitors Available for Administration to Small Animals in the United States

*

Doses have not been extensively tested and are extrapolated from human and small animal data. Further studies are needed to confirm these dosages.

†This form of the drug has not been commonly use in small animal. Further studies are needed to characterize the properties of these formulations.

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The pharmacokinetics of the delayed and immediate-release form of PPIs have been studied in human medicine. Immediate-release forms reach peak concentrations faster and have higher plasma peak concentrations but overall similar areas under the curve (a surrogate for efficacy) compared to the delayed forms.³¹ In dogs and cats, oral administration of omeprazole as enteric coated tablets, split enteric coated tablets, capsules with enteric coated granules, bicarbonate suspension (2 mg of omeprazole/mL of 8.4% sodium bicarbonate), and oral paste suspensions^a (suspended in a 1:9 sesame oil ratio suspension at 40 mg/ml for dogs or suspended at 1:39 ratio of cod liver oil at 10 mg/ml in cats) have been studied.^{28,30,32–34} All these formulations cause significant acid suppression without one formulation being clearly superior to another. Similarly, enteric coated tablets and oral paste suspension in dogs as well as split tablets and oral suspension in cats all reached similar omeprazole plasma levels.^32,34 It should be noted, however, that the efficacy of the different formulations in promoting ulcer healing in dogs and cats have not been compared.

Thus, the easiest PPI dosing strategies to use in small dogs and cats would be the 2 mg/ml bicarbonate solution, dilute equine oral paste in sesame or cod oil, or administration of microgranules/pellets from an unsealed capsule. Less ideal would be the administration of a fraction of an enteric coated tablet. Large dogs or cats (>10 kg) should receive the whole tablet or capsule or, if needed, one of the previously described solutions, ideally without altering the formulation.

The bioavailability of omeprazole in humans is relatively good, ranging from 40–58%.³⁵ The PPIs exert a linear dose/response relationship up to a maximal effect, after which an increase in dosage does not result in an increase in efficacy.²⁶ In humans, food does not impact overall efficacy.³⁶ In humans and small animals, PPIs have a rapid clearance and very short plasma half-life (approximately one hour).^34,35,37,38 Despite this very short half-life, PPI's pharmacodynamics effect is extended (24 to 48 hr) since they cause irreversible inhibition of the H⁺/K+ ATPase pumps.^30,37,39,40 The maximal efficacy of PPIs are considered to be reached after 3–4 days of administration, and administration is usually recommended 30 min before a meal in order to maximize the number of activate ATPase pumps inhibited.^37,41,42

The PPIs are primarily metabolized by hepatic oxidation through the cytochrome CYP450 enzymes with subsequent renal excretion of inactive metabolites.⁴³ Omeprazole and esomeprazole significantly inhibit the CYP450 system, which can alter the metabolism of other drugs metabolized by the same enzymes.⁴⁴ In humans, there are individual variations in CYP450 metabolism of PPI, which can lead to different plasma concentrations and alter the response to acid suppression.⁴⁴ The kinetics of the hepatic metabolism of PPIs have not been investigated in dogs and cats.

Side Effects

In dogs and cats, short-term use of PPIs appears to be well tolerated. Diarrhea and vomiting have been occasionally reported in dogs, but not cats.^{28,30,32,34,41,45,46} In humans, short term use of PPIs is associated with headache, gastrointestinal upset, rash, and dizziness.⁴⁷

The risks of long-term use of PPIs in dogs and cats have been poorly characterized. In humans, long-term use has been associated with multiple comorbidities. These include increased risk of fractures, pneumonia, Clostridium difficile infection, vitamin B12 deficiency, kidney disease, and the occurrence of gastric neoplasia.^48,49 Increased fracture risk (especially in adults with osteoporosis) with long-term PPI use in humans may be secondary to the fact that gastric acidity is essential for intestinal absorption of calcium and magnesium. Thus, humans on long-term PPI therapy can become hypomagnesemic.^48,50,51 In a recent article investigating the influence of a 60-day course of omeprazole (5 mg orally q 12 hr) in cats, no significant difference in biochemistry, blood count, and bone density were detected.⁵² However, due to the low number of cats included in the study and the duration of treatment, the effect of long-term acid suppressive therapy on bone metabolism remains unknown in small animals.

The use of PPIs leads to changes in the intestinal microbiome which may be associated with an increased risk of pneumonia, enteric Clostridium difficile infection, or spontaneous bacterial peritonitis.^48,53–55 A single study has evaluated the effect of omeprazole (1.1 mg/kg q 12 hr PO) administration on the gastrointestinal bacterial population in dogs.⁵³ A decrease in the gastric abundance of Helicobacter spp. and an increase in the relative abundance of Proteobacteria, Firmicutes, and Fusobacteria in the stomach during omeprazole treatment was noticed, but there was no effect on the total number of gastric bacteria.^53,56 In contrast, there was no change in the overall phylogenetic composition of the microbiota in the duodenum, but there was an increase in the total number of bacteria. In a study investigating the pharyngeal flora in dogs treated with omeprazole (1 mg/kg q 24 hr for 12 days PO), there was a significant increase of several bacterial species (Staphylococcus spp., Bacillus spp., and Pasteurella spp.), whereas the total number of bacterial species did not change.⁵⁶ No adverse consequences of these changes in the microbiome of the digestive tract have been reported in dogs, although it is possible that this dysbiosis could be responsible for the development of diarrhea in some dogs on PPI therapy.^30,32,45

In humans, acute interstitial nephritis is a rare side effect. In addition, a recent publication found an increased risk of developing chronic kidney disease in patients on long-term PPI but not in those on H2-RA. The pathophysiological mechanisms for these kidney derangements remain unclear.^43,49 Studies have not examined the impact of chronic PPI therapy on acute and chronic kidney injury in dogs and cats.

Vitamin B12 deficiency occurs in people using long-term PPI and H2-RA due to decreased release of the vitamin from the dietary proteins.⁵⁷ No cobalamin deficiency was detected in cats treated with omeprazole (5 mg orally q 12 hr) for 60 days.⁵² The influence of omeprazole on cobalamin status in dogs has not been reported.

Due to the occurrence of gastric neoplasia in laboratory rodents on long-term PPI therapy, PPIs were initially approved only for short term use (2 wk). However, post-marketing surveillance has not shown a relationship between gastric cancer (such as carcinoma or gastric carcinoid) in humans.⁴⁷ Similarly, high doses of pantoprazole were safely given to neonatal dogs for 13 wk, and no neoplastic transformation was noticed in beagles receiving long-term (7 yr) low-dose (0.17 mg/kg q 24 hr) omeprazole.^58,59 In a recent publication, administration of omeprazole (5 mg orally q 12 hr) for 60 days was well tolerated in healthy cats.⁵² In that publication, rebound gastric hyperacidity was detected after drug discontinuation in the two cats in which the gastric pH was monitored.⁵²

Drug Interactions

Similar to H2-RA, drug interactions with PPIs can be secondary to an increase in gastric pH or from cytochrome P450 inhibition.⁴⁴ In addition, interactions with the drug efflux transporter P-glycoprotein have been reported.⁶⁰ P-glycoprotein is a membrane-bound ATP-dependent drug transporter present on epithelial cells. PPIs can partially inhibit P-glycoprotein drug efflux and, thus, potentially increase the level of drugs that are substrates for it. However, the clinical impact of this interaction remains unknown at this time.⁶¹

In humans, clinically significant drug interactions due to cytochrome P450 inhibition have been reported with numerous drugs, including benzodiazepines and warfarin.^6,44 When used concomitantly, PPIs reduce the metabolism of these drugs and increase their pharmacological effects. PPI-induced increases in gastric pH can decrease absorption of ketoconazole, iron, or digoxin by reducing their solubility.^6,60 Further concerns have been raised regarding the interaction between PPIs and clopidogrel and mycophenolate mofetil.^62,63 In humans, use of PPIs is associated with decreased mycophenolate absorption, but the clinical impact of this interaction remains controversial.^60,62 Use of omeprazole has also been associated with decreased efficacy of clopidogrel, leading to the concern of an increased risk of thromboembolic events when used concomitantly. The clinical implication of this finding is still under investigation, although a black box warning for the use of the drugs together has been issued by the Food and Drug Administration. This drug interaction with clopidogrel is limited to co-therapy with omeprazole and not other PPIs.^63,64

Acid Suppressive Therapy Use in Healthy Animals

The efficacy of H2-RA and PPIs have been investigated in experimental settings in dogs and cats.^{28,30,32,34,39,41,53,65–71} In human medicine, efficacy of acid suppressive treatment is defined by measurement of the gastric pH with an endpoint of a gastric pH >3 for at least 75% of the day to heal duodenal ulceration, and a pH >4 for at least 66% of the day for gastro-esophageal reflux.^72,73 These end points originate from human studies that determined the optimal gastric pH to achieve the therapeutic goal of gastric/esophageal ulcer/erosion healing. Many veterinary studies have used these human end points to evaluate H2-RA's and PPI's efficacy in small animals, even though no studies have confirmed that these end points maximize ulcer or reflux healing in small animals.^{28,30,32,34,41}

In a randomized controlled crossover study in healthy beagles, ranitidine at 2 mg/kg IV twice a day did not significantly raise median gastric pH or increase the percentage of time that intragastric pH was >3 compared to placebo.³⁰ Similar concerns about the efficacy of ranitidine in dogs were also raised in two other studies.^65,66 The efficacy of cimetidine is considered low in dogs and was not superior to placebo when given orally between 3 and 7.5 mg/kg TID in an experimental study performed on beagles with acetylsalicylic acid-induced ulcerations.^6,74 Results of studies investigating the effect of famotidine on canine gastric pH are somewhat contradictory. An early study in a canine gastric pouch model showed that famotidine partially inhibited acid production in dogs. However, the famotidine doses ranged from 0.3 to 100 mg/kg, and the response in this model is difficult to apply clinically.⁶⁸ Another study confirmed the efficacy of famotidine (0.5 mg/kg IV q 12 hr) to increase the gastric pH of healthy beagles. In this study, famotidine significantly increased the mean gastric pH and the percentage of time with a gastric pH >3 (48.9–60.1%) or >4 (30.5–48.4%) compared to placebo.³⁰ However, these outcomes did not reach the level of pH control recommended in human medicine.³⁰ Surprisingly, in one experimental study in a mixed breed colony of dogs, high dose oral famotidine (1 mg/kg q 12 hr) failed to induce any significant acid suppression.³²

Recent publications have investigated the efficacy of ranitidine and famotidine in cats.^28,34 Ranitidine (1.5–2.3 mg/kg q 12 hr orally) did not show any superior efficacy in raising gastric pH compared to placebo in eight healthy domestic shorthair cats.²⁸ Famotidine (0.88–1.26 mg/kg q 12 hr orally), however, led to a significant increase in the duration of time intragastric pH >3 compared to placebo.³⁴ Similar to dogs, these results did not reach the efficacy end point recommended in humans for treatment of gastro-esophageal reflux disease or duodenal ulcer.^30,34

Recent studies also investigated the efficacy of PPIs for acid control in dogs and cats.^{28,30,32,34,41,66} In healthy mixed-breed dogs, beagles, and Labrador retrievers, omeprazole and pantoprazole were effective in increasing gastric pH.^30,32,41,66 No significant difference in the percentage of time gastric pH was >3 or 4 was found between IV famotidine (0.5 mg/kg q 12 hr), pantoprazole (1 mg/kg q 24 hr IV), and oral omeprazole (1 mg/kg q 24 hr).³⁰ The one exception was on day 2, when omeprazole was better than famotidine. However, omeprazole significantly increased gastric pH compared to famotidine, ranitidine, and placebo in two studies.^32,66 In one additional study, IV famotidine given in addition to pantoprazole did not improve the efficacy over the use of the same dose of pantoprazole alone (1 mg/kg IV q 12 hr).⁴¹ Noteworthy is the fact that many of these studies that used doses up to 2.6 mg/kg once a day still failed to meet the human guidelines for pH control.^30,32 Experimental studies including gastric fistula dogs treated with esomeprazole (1.6 mg/kg once intraduodenally) and lansoprazole (0.1–3 mg/kg once orally) also report similar acid suppression compared to omeprazole.^70,71 Of the previously discussed studies, only dogs receiving oral omeprazole (1 mg/kg) or intravenous pantoprazole (1 mg/kg) twice a day reached the acid suppression requirement recommended in humans.^30,32,41

At this time, two studies have looked at the efficacy of PPIs in suppressing acid production in cats. In healthy cats, once-daily oral omeprazole (1.1–1.3 mg/kg) failed to show any significant efficacy compared to placebo.²⁸ However, twice-daily oral omeprazole (1 mg/kg) given as microgranules, fractionated tablets, or paste suspension revealed significant acid suppression compared to oral famotidine (1 mg/kg q 12 hr ) or oral ranitidine (1.5–2.3 mg/kg q 12 hr) and approached but did not reach the recommended human guidelines.^28,34 The efficacy of twice-daily omeprazole in cats remained similar regardless of the type of formulations used (paste, fractionated tablets, or granules).

In conclusion, PPIs appear to be superior to H2-RAs in suppressing acid production in small animals. Omeprazole or pantoprazole given at 1 mg/kg twice daily are recommended to achieve appropriate acid control. For H2-RA therapy, famotidine (at least 1 mg/kg q 12 hr) is the drug of choice. Based on available evidence, ranitidine cannot be recommended at this time for gastric acid control in small animals.

Acid Suppressive Therapy and NSAID treatment

It is well established both in small animals and human medicine that nonsteroidal anti-inflammatory drug (NSAIDs) are ulcerogenic and can have potentially serious gastrointestinal side effects (see part 1 of this review).^75–79 In human medicine, administration of acid suppressive therapy can decrease the gastroduodenal morbidity associated with the use of NSAIDs.^78,80,81 Despite the extensive literature available in human medicine, the optimal acid suppressive therapy and the target population requiring systematic gastro-protection in dogs and cats being treated with NSAIDs remains unclear. Contrary to human medicine, no controlled studies in small animals have studied the benefit of concurrent acid suppressive therapy in small animals treated with NSAIDs. However, one small experimental study did not show any benefit of cimetidine (10 mg/kg orally q 8 hr) or omeprazole (0.7 mg/kg orally q 24 hr) in reducing acetylsalicylic acid-induced gastritis (25 mg/kg orally q 24 hr) over a 20-day treatment course.⁶⁹ Another study in dogs also failed to show any benefit of using cimetidine (7.5 mg/kg orally q 8 hr) to prevent acetylsalicylic acid-induced gastric hemorrhage.⁷⁴

Due to the paucity of the data available in small animal medicine, recommendations regarding the concurrent administration of NSAIDs and acid suppressive therapy cannot be clearly established at this time.

Acid Suppressive Therapy in Strenuous Exercise

Similar to horses and humans, strenuous exercise can induce gastritis and gastric ulceration in Alaskan sled dogs.^82–85 Omeprazole (1 mg/kg) or famotidine (1 mg/kg) given once a day orally significantly decreased the severity of gastric lesions in exercising sled dogs.^10,45 In a separate study, the same dose of famotidine failed to reduce the severity of gastric lesions or the occurrence of gastric bleeding evaluated via upper gastrointestinal endoscopy, but did decrease the prevalence of gastric lesions (classified as the number of discolored areas or bleeding lesions).⁸⁶ When oral high-dose famotidine (2 mg/kg q 12 hr) was compared to omeprazole (1 mg/kg q 24 hr) in a randomized trial, omeprazole was superior in reducing the severity and the prevalence of gastric lesions.⁸⁶ Despite its effect on the severity of gastric lesions, omeprazole did not improve overall performance status.⁸² In addition, omeprazole led to a significantly higher frequency of diarrhea than placebo in one study.⁴⁵ In conclusion, there is good evidence that omeprazole, used once or twice daily at 1 mg/kg daily, decreases gastric lesion in sled dogs. However, this was not accompanied by conclusive evidence of improvement in the dog's performance.

Acid Suppressive Therapy in Reflux Esophagitis

In healthy dogs, there is evidence of decreased esophageal pH and increased esophageal reflux during anesthesia.^87,88 In one study, ranitidine (2 mg/kg IV) 6 hr before anesthesia did not increase the pH of reflux in dogs.⁸⁸ In two randomized placebo-controlled studies, omeprazole (1 mg/kg orally) given 4 hr before, or esomeprazole (1 mg/kg IV) administered twice, once at 12–18 hr prior to anesthesia and again 1–1.5 hr before induction, significantly raised esophageal pH compared to placebo.^33,89 Thus, PPI use should be considered as a therapeutic option to prevent consequences associated with acid reflux during anesthesia.

Acid Suppressive Therapy in Spinal Cord Injury

There is a high prevalence of gastric lesions in dogs with acute spinal injury (up to 76% in some studies).^90,91 In a randomized placebo-controlled study of dogs with acute intervertebral disc disease treated with both surgery and corticosteroids and given omeprazole at 0.7 mg/kg once a day orally, there was no decrease in the prevalence or severity of gastric lesions.⁹⁰ Failure to find a beneficial effect of omeprazole may be related to an inappropriately low dose of omeprazole or the fact that gastric ulceration in dogs with spinal cord injury occurs by a non-acid-dependent mechanism. There is a need for more studies investigating the use of acid suppressive therapy medications, particularly higher doses of PPIs (1 mg/kg q 12 hr) in dogs with spinal injury.

Acid Suppressive Therapy: Miscellaneous Use

Indication for Treatment

In human medicine, H2-RAs and PPIs are among the most commonly prescribed medications.^104,105 The reasons for this include the high incidence of stress-associated mucosal disease in ICU patients, Helicobacter infection and associated ulcer disease, and gastroesophageal reflux disease. These indications, combined with the fact that these medications are well tolerated, easily accessible, and relatively inexpensive, have led to H2-RAs and PPIs being two of the most prescribed medications in humans.^104,105 This is not trivial, as these medications are not totally free of side effects. They can be associated with significant drug interactions, cause changes in the microbiome, and negatively impact compliance.^30,32,45

Despite the multiplicity of studies in human medicine, guidelines for the use of acid suppressor therapy in humans are lacking, and those that do exist are controversial. Current guidelines from the American Journal of Health-System Pharmacy and the American College of Cardiology Foundation apply only to a small set of patients (stress ulcer prophylaxis and reducing the risk of anti-platelet therapy, respectively).^106,107 In humans, risk factors for stress-related mucosal ulceration have been defined.^106,108,109 In veterinary medicine, the existence of stress-related mucosal ulceration in critically ill patients is still poorly defined, so it is difficult to know if human guidelines would apply. The human guidelines include absolute indications such as respiratory failure with mechanical ventilation, the presence of coagulopathy (thrombocytopenia, prolonged coagulation times), previous GI bleeding, severe head or spinal cord injury, major surgery, and acute lung injury.^110–112 In addition, relative indications include risk factors that alone would be unlikely to be significant, but when combined, could lead to gastroduodenal ulceration.

In addition to known morbidities, certain clinical and clinical pathologic findings are also considered good surrogates or markers for an increased relative risk of developing gastrointestinal pathology/bleeding. In humans, these markers include significant hypotension (below 100 mm Hg), serum urea nitrogen:creatinine ratio of more than 30 (urea increasing due to digestion of blood by the gastrointestinal tract), and severe anemia (packed red blood cells below 20%).^113–115 Unfortunately, similar studies have not been done in dogs and cats. Increased blood urea nitrogen (BUN)/creatinine ratio >20 (mean BUN/creatinine = 34) and the presence of coagulopathy, however, have been associated with an increased risk of gastrointestinal bleeding in dogs.¹¹⁶ In a recent study, anemia was associated with a worse outcome in critically ill dogs, although the anemia was not clearly linked with gastrointestinal bleeding.¹¹⁷

Based on the available literature on acid suppressive therapy, several recommendations can be made for the use of these drugs in dogs and cats (Tables 2 and 3).

TABLE 2 Proposed Absolute Indications for Acid Suppressive Treatment in Small Animals

NSAID, nonsteroidal anti-inflammatory drug.

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TABLE 3 Proposed Relative Indications for Acid Suppressive Treatment in Small Animals (2 Required)

NSAID, nonsteroidal anti-inflammatory drug.

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Acid suppressive therapy should be prescribed in dogs and cats with or at high risk of developing gastric ulceration or bleeding.^104,106,110 Proposed absolute indications for acid suppression are summarized in Table 2.^{104,116,118–125} Proposed relative indications (two comorbidities required in the same patient in order to justify prophylactic use of acid suppressive therapy) for the use of acid suppressive therapy are summarized in Table 3.^{90,104,109,110,113–116,118,120,126–128} In addition, a high serum BUN-to-creatinine ratio, a packed red blood cells of less than 20, and severe hypotension are also indicators for a high risk of having or developing ulcerative disease.

These proposed guidelines in dogs and cats should be considered as preliminary, and further studies prospectively investigating an experimental model for gastroduodenal ulceration/bleeding, or clinical studies, should be performed in small animals to validate these recommendations.

Type, Dose, and Duration

In small animals, a sufficient body of information is available to make recommendations on the use of H2-RAs ranitidine and famotidine and the PPIs omeprazole and pantoprazole. Based on the literature in dogs, only omeprazole and pantoprazole (1 mg/kg q 12 hr given orally or intravenously) have the ability to provide acid suppressive activity close to what is recommended in human medicine for ulcer healing. In dogs and cats intolerant of oral medication, intravenous pantoprazole (1 mg/kg q 12 hr) is recommended for acid suppression. In human medicine, actively bleeding patients are sometimes treated with an initial bolus (80 mg) of pantoprazole followed by a high continuous rate infusion of a PPI (8 mg/hr infusion), with the goal of maintaining the gastric pH above 6 at all times.^129,130 These recommendations are based on the observation that attainment of full coagulation is unlikely to occur in an acid environment. No publications have studied the efficacy of this protocol in small animals.¹³¹ Based on the hepatic metabolism and the current human medicine recommendations, it is likely that no dose adjustments for decreased renal function are needed in small animals, but further studies are required to confirm this recommendation.⁴³ Currently, there are no recommendations regarding dose adjustment of acid suppressive drugs with liver disease/failure in small animals.

Based on currently available literature, for H2-RA therapy ranitidine (and cimetidine) cannot be recommended for acid suppression in dogs.^{6,28,30,65,66,74} Among H2-RA, famotidine (minimum 1 mg/kg q 12 hr IV or oral) appears to offer the best control of gastric acid secretion. Parenteral administration may be more efficacious than oral in some dogs.^32,86 Famotidine may be substituted in dogs that are intolerant to PPIs, when there is a high likelihood of PPI drug interaction, or when a PPI is not available. In the presence of azotemia, famotidine dosages should be adjusted according to the level of azotemia to limit potential side effects and accumulation of the drug.¹⁹ Based on a recent publication, concomitant use of pantoprazole and famotidine in dogs does not appear to increase the acid suppressive effect over pantoprazole alone.⁴¹

Similar to dogs, in cats, omeprazole or pantoprazole at 1 mg/kg q 12 hr IV or PO are the therapy of choice for acid suppression.^28,34 Neither twice-a-day oral ranitidine nor oral famotidine has shown significant acid suppressant activity.^28,34

The appropriate duration of treatment for naturally acquired gastric ulceration in dogs and cats is unknown, but it is reasonable to suggest a treatment of 4–8 wk, similar to what is reported in human medicine, in which the inciting comorbidity has been eliminated.¹²⁹ However, no precise data on clinical healing time for ulcers in dog and cats is available. Two studies on experimentally induced gastric ulceration in dogs showed that 14–17 days of treatment with oral omeprazole (2mg/kg q 24 hr) was sufficient for healing.^132,133 In another study, mechanically induced ulcers healed between 15 and 20 days after induction in dogs receiving oral acetylsalicylic acid (25 mg/kg dose), regardless of the treatment implemented (control, cimetidine 10 mg/kg orally q 8 hr or omeprazole 0.7 mg/kg orally q 24 hr).⁶⁹ The duration of treatment should also take into account the risk of rebound gastric hyperacidity, as it has been described in two cats at discontinuation of omeprazole after 60 days of treatment.⁵² This rebound gastric acidity has been commonly described in human medicine, but the clinical significance of this finding remains unknown at this time.¹³⁴ Some authors in human medicine have recommended tapering the PPI treatment in order to decrease rebound gastric acidity, but the benefit is still unclear.¹³⁵ Further studies with larger numbers of patients and outcome assessment not limited to the measure of gastric pH are needed to determine if a tapering course of PPI should be recommended in small animals.