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Treating equine gastric ulcers

Author : ANDY DURHAM

Categories : Vets

Date : June 2, 2014

ANDY DURHAM BSc, BVSc, CertEP, DEIM, DipECEIM, MRCVS provides readers with a selection of techniques for treatment of lesions found in the of a horse – from pharmacotherapy to nutritional aids

ALTHOUGH gastric lesions may be seen almost anywhere in the equine stomach, certain areas are predisposed. In adult horses these comprise the squamous mucosa, close to the margo plicatus at the lesser or greater curvatures, and also the glandular mucosa in the peripyloric region (Figure 1).

Clinical signs associated with gastric ulcers are not specific and can always potentially be explained by other non-gastric factors. Thus far, investigation of potential diagnosis via blood or urine sampling has not proved useful (for example, O’Conner et al, 2004) and, therefore, diagnosis depends entirely on gastroscopy.

The commonly affected areas of squamous mucosa are more likely to be exposed to the ventral pool of acidic gastric fluid and thus, squamous mucosal ulcers may straightforwardly be a consequence of exposure in this relatively poorly defended region of the stomach. Thus, risk factors for squamous mucosal ulceration comprise factors that are likely to increase acid contact and injury.

In contrast, it is difficult to conceptualise identical risks for glandular peripyloric ulcers, which occur in a region that is normally almost constantly exposed to and, consequently, has evolved numerous defensive mechanisms to resist this. Nevertheless, even though acid exposure seems an unlikely causal factor for peripyloric ulcers, intuitively it makes sense acid suppressant

1 / 12 should aid healing in this area. It should also be considered that effective acid control might decrease ulcer-associated pain, even when healing is not yet achieved.

Hydrochloric acid is secreted almost constantly by parietal cells in the glandular mucosa, in response to stimulation of acetylcholine and histamine H2-receptors leading to activation of the H+/K+ adenosine triphosphatase (ATPase) proton pump mechanism. There are essentially two classes of drug that suppress acid production in the stomach – H2-receptor antagonists and direct proton pump inhibitors (PPIs). In horses, only the latter category is licensed for use and, furthermore, the effects of the PPIs tend to be greatly superior to other drugs. Additional therapeutic aids include coating/barrier agents and acid buffering products.

Proton pump inhibitors

Although several drugs exist in the PPI class, is undoubtedly the best used and understood in horses. Omeprazole paste is a reversible blocker of the H+/K+ ATPase, which has dose and time-dependent effects on acid production. It has been shown to suppress gastric acid secretion for 24 hours in horses at a dose of 4mg/ kg orally (Daurio et al, 1999) and several studies have indicated 70 per cent to 90 per cent healing of squamous mucosal ulcers after a month of treatment, which is superior to H2 antagonists (Murray et al, 1997; Andrews et al, 1999; MacAllister et al, 1999; Lester et al, 2005).

In cases where oral treatment is not considered desirable (for example, grass sickness, oesophageal injury or other causes of dysphagia), then omeprazole can be given intravenously at 0.5mg/kg to 1mg/kg once a day (Andrews et al, 2006a).

The required dose and duration of omeprazole treatment is likely to depend largely on whether the risk factors that have led to ulcer development are effectively controlled. Clearly, there will be large differences in response rates and times between horses maintained in normal race training and feeding versus those that are laid off work and turned out in a field during treatment.

Indeed, evidence suggests ulcers can heal within a week or two of treatment if causal management factors are corrected, whereas a month of treatment is more commonly required in working horses (Murray, 1994). It is, therefore, generally advised horses are re-gastroscoped two weeks after treatment commences, so can be adjusted or even stopped as necessary. If this is not possible then at least 28 days’ therapy is advisable. Clinical response should not be taken to indicate complete ulcer healing, as acid suppression appears to reduce pain, even when ulcers are still present. Frequently, lower doses of 1mg/kg to 2mg/kg daily are adequate alongside good management.

Following the loss of patent of the first licensed omeprazole paste, it is to be expected other omeprazole products will enter the equine market at presumably competitive prices. Experience in other countries has indicated not all omeprazole products are equally efficacious and

2 / 12 gastroprotection of the acid-labile omeprazole drug is probably an important factor in . Nevertheless, some alternative products have been shown to be effective when buffered (Merritt et al, 2003) and, hopefully, evidence will be available to reassure practitioners of such with future products.

H2-receptor antagonists

The H2-receptor antagonists class of drugs is not licensed for use in horses and, therefore, the obligations of the medicines cascade should be considered prior to their use. is one of the oldest antiulcer on the market and, therefore, is less costly than others. Although some limited evidence of efficacy exists, it is not commonly used in horses and has little to recommend it.

Ranitidine is significantly more potent than cimetidine with better evidence to support its use in horses. However, three times daily dosing at a dose of 6.6mg/kg orally is required for reasonable efficacy, which frequently makes it less attractive (Holland et al, 1997; Murray et al, 1993). Newer H2-receptor antagonists such as have the benefit of allowing twice daily dosing, although they can be cost prohibitive (Duran, 1999).

Coating/ barrier agents

Barrier function and dysfunction may be a crucial component of ulcerogenesis in some horses and use of artificial barrier agents may promote healing alongside acid suppressant therapy. Sucralfate, a hydroxyl-aluminum salt of sucrose octasulfate, is the most commonly used such product. Sucralfate is transformed from a white liquid into a sticky gel at low pH and binds to ulcers, offering physical protection (Figure 2) in addition to increasing bicarbonate secretion and production (Borne and MacAllister, 1993).

Although sucralfate is unlikely to be very efficacious alone, it is commonly used alongside acid suppressive therapy in glandular (pyloric) ulcers. Apolectol, a pectin-lecithin complex, has also been subject to some trials where a beneficial barrier function is also claimed (Venner et al, 1999) and is contained in several feed supplements.

Antimicrobials

Helicobacter species have not been shown to cause gastric ulcers in horses and, although many ulcers are often seen to be invaded by multiple bacterial species, this does not necessarily implicate the bacteria in causation. The equine stomach normally contains a high bacterial load (Al Jassim et al, 2005), many of which are acid tolerant and it should be no surprise then that they are found – perhaps opportunistically – in areas of mucosal compromise.

3 / 12 Although evidence in other species supports the use of antimicrobials in promoting healing of infected ulcers (Elliot et al, 1998), this remains contentious in horses (Al Jassim et al, 2008; Sykes, 2013) and some bacteria (for example, Gram-positive lactobacilli and streptococci) may even have a beneficial effect on ulcer healing (Elliot et al, 1998; Al Jassim et al, 2008). Responsible use of antimicrobials dictates more evidence of benefit and indication in cases of gastric ulceration should be sought prior to routine usage.

Other drugs

Prostaglandin E analogues, such as , have been used to treat gastroduodenal ulcers in man and have a sound basis for treatment of glandular (pyloric) ulcers in horses, as this is a prostaglandin-dependent area in the equine stomach. Doses of 5mcg/kg orally every eight to 12 hours have been used in horses and shown to raise gastric pH (Sangiah et al, 1989).

Concerns have arisen – especially in human medicine – that long-term acid suppression might lead to a compensatory response in the form of hypergastrinaemia with subsequent hyperplastic, dysplastic or even neoplastic change in the stomach.

Octreotide is an analogue of somatostatin, which has been used to inhibit gastrin secretion and indirectly inhibit acid production. This has been used effectively in humans where concerns of hyperplasia exist, but is too costly for use in horses. In any event, gastric hyperplasia is not recognised in horses on long-term acid suppression.

Calcium and magnesium-based antacid products might aid in the maintenance of higher gastric pH, but, owing to the constant nature of acid secretion in horses, are unlikely to be effective as sole therapy unless administered every couple of hours.

Dietary management

Gastric ulcers are most likely to be a disease of domestication and management, and therefore have an inherent risk of recurrence unless ulcerogenic risk factors are controlled. Therefore, in addition to pharmacotherapy discussed above, management and dietary changes should be implemented as far as the required use of the horse allows. Free access to forage helps maintain pH stratification in the stomach, so that the squamous mucosa is protected from gastric acid (Figure 3 ). This effect is probably at its most important during fast exercise when acid splashing is inevitable if the stomach is empty or poorly filled (Figure 4; Lorenzo-Figueras and Merritt, 2002). Forage quality is also important, with evidence suggesting a beneficial effect of feeding alfalfa versus bromegrass hay or coastal Bermuda grass hay (Nadeau et al, 2000; Lybbert et al, 2007), and of hay or haylage versus straw (Luthersson et al, 2009).

An epidemiologic study found forage feeding intervals greater than six hours represented the strongest dietary risk factor (greater than five times risk) for ulceration of the gastric squamous

4 / 12 mucosa (Luthersson et al, 2009). Given the marked anatomic and physiologic differences between the human and equine gastrointestinal tracts, the anthropomorphic assumption that fast work is best undertaken on an empty stomach is both unfounded and potentially injurious to the equine stomach.

Forage feeding should be encouraged right up to the onset of fast exercise training, although the argument for weight reduction associated with forage withholding is harder to counter during a competition or race. It is generally assumed grazing reduces the risks of gastric ulceration in horses, presumably due to similar mechanisms as those previously described for forage feeding. However, grazing horses are encountered that have severe squamous mucosal and/or pyloric ulceration (le Jeune et al, 2006; Bell et al, 2007), so this relationship is not totally clear and might depend on factors such as pasture fructan and simple sugar content, which might possibly promote acid injury under certain circumstances. Associations between cereal feeding and ulceration of the gastric squamous mucosa are well recognised (Coenen, 1990; Andrews et al, 2006b). An epidemiologic study found consuming more than 1g starch per kg bodyweight per meal (for example, 1kg to 2kg concentrates or cereal for a 500kg horse) more than doubled the risk of having squamous mucosal ulcers (Luthersson et al, 2009).

Theoretically beneficial mechanisms of action of dietary oils in high-fat feeds might include provision of substrate for prostaglandin synthesis (likely to primarily aid gastric glandular mucosal defence) or possibly by binding potentially injurious lipophilic short chain fatty (SCFAs) and acids within the gastric fluid. Possible increases in gastric emptying rates may also be found in horses fed high-fat versus high-starch diets, thereby potentially limiting SCFA accumulation (Lorenzo-Figueras et al, 2005). Although one study found reduced gastric acid secretion and higher levels of potentially gastroprotective in horses fed small amounts (45ml) of corn oil (Cargile et al, 2004), a further study that involved feeding higher levels of dietary fat found no benefit on ulcer severity (Frank et al,2005).

• Please note some drugs mentioned within this article are not licensed for use in horses and are used under the cascade.

References

Al Jassim R A, Scott P T, Trebbin A L et al (2005). The genetic diversity of lactic acid- producing bacteria in the equine , FEMS Microbiol Lett 248(1): 75-81. Al Jassim R A, McGowan T, Andrews F et al (2008). Gastric ulceration in horses – the role of bacteria and lactic acid, Rural Industries Research and Development Corporation, Final Report: 1-26. Andrews F M, Sifferman R L, Bernard W et al (1999). Efficacy of omeprazole paste in the treatment of gastric ulcers in horses, Equine Vet J Suppl 29: 81-86. Andrews F M, Frank N, Sommardahi C S et al (2006a). Effects of intravenously administered omeprazole on gastric juice pH and gastric ulcer score in adult horses, J Vet

5 / 12 Intern Med 20(5): 1,202-1,206. Andrews F M, Buchanan B R, Smith S et al (2006b). In vitro effects of and various concentrations of acetic, propionic, butyric or valeric acids on bioelectric properties of equine gastric mucosa, Am J Vet Res 67(11): 1,873-1,882. Bell R J, Kingston J K, Mogg T D et al (2007). The prevalence of gastric ulceration in racehorses in New Zealand, N Z Vet J 55(1): 13-18. Borne A T and MacAllister C G (1993). Effect of sucralfate on healing of subclinical gastric ulcers in foals, J Am Vet Med Assoc 202(9): 1,465-1,468. Cargile J L, Burrow J A, Kim I et al (2004). Effect of dietary corn oil supplementation on equine gastric fluid acid, sodium, and prostaglandin E2 content before and during pentagastrin infection, J Vet Intern Med 18(4): 545-549. Coenen M (1990). The occurrence of feed-induced stomach ulcers in horses, Schweiz Arch Tierheilkd 132(3): 121–126. Daurio C P, Holste J E, Andrews F M et al (1999). Effect of omeprazole paste on gastric acid secretion in horses, Equine Vet J Suppl 29: 59-62. Duran S H (1999). Famotidine, Compend Cont Ed Pract Vet 21(5): 424-425. Elliott S N, Buret A, McKnight W et al (1998). Bacteria rapidly colonise and modulate healing of gastric ulcers in rats, Am J Physiol 275(3 Pt 1): 425-432. Frank N, Andrews F M, Elliot S B et al (2005). Effects of dietary oils on development of gastric ulcers in mares, Am J Vet Res 66(11): 2,006-2,011. Holland P S, Ruoff W W, Brumbaugh G W et al (1997). Plasma of HCI in adult horses, J Vet Pharmacol Ther 20(2): 145-152. le Jeune S S, Nieto J E, Dechant J E et al (2006). Prevalence of gastric ulcers in Thoroughbred broodmares in pasture, Proc Am Assoc Equine Pract 52: 264. Lester G D, Smith R L and Robertson I D (2005). Effects of treatment with omeprazole or ranitidine on gastric squamous ulceration in racing Thoroughbreds, J Am Vet Med Assoc 227(10): 1,636-1,639. Lorenzo-Figueras M and Merritt A M (2002). Effects of exercise on gastric volume and pH in the proximal portion of the stomach of horses, Am J Vet Res 63(11): 1,481-1,487. Lorenzo-Figueras M, Preston T, Ott E A et al (2005). Meal-induced gastric relaxation and emptying in horses after ingestion of high-fat versus high-carbohydrate diets, Am J Vet Res 66(5): 897-906. Luthersson N, Nielsen K H, Harris P et al (2009). Risk factors associated with equine gastric ulceration syndrome (EGUS) in 201 horses in Denmark, Equine Vet J 41(7): 625-630. Lybbert T, Gibbs P, Cohen N et al (2007). Feeding alfalfa hay to exercising horses reduces the severity of gastric squamous mucosal ulceration, AAEP Proceedings 53: 525-526. MacAllister C G, Sifferman R L, McClure S R et al (1999). Effects of omeprazole paste on healing of spontaneous gastric ulcers in horses and foals: a field trial, Equine Vet J Suppl 29: 77-80. Merritt A M, Sanchez L C, Burrow J A et al (2003). Effect of GastroGard and tree compounded oral omeprazole preparations on 24 h intragastric pH in gastrically cannulated

6 / 12 mature horses, Equine Vet J 35: 691-695. Murray M J (1994). Equine model of inducing ulceration in alimentary squamous epithelial mucosa, Dig Dis Sci 39(12): 2,530-2,535. Murray M J and Schusser G F (1993). Measurement of 24-h gastric pH using an indwelling pH electrode in horses unfed, fed and treated with ranitidine, Equine Vet J 25(5): 417-421. Murray M J, Haven M L, Eichorn E S et al (1997). Effects of omeprazole on healing of naturally occuring gastric ulcers in Thoroughbred racehorses, Equine Vet J 29(6): 425-429. Nadeau J A, Andrews F M, Mathew A G et al (2000). Evaluation of diet as a cause of gastric ulcers in horses, Am J Vet Res 61(7): 784-790. O’Conner M S, Steiner J M, Roussel A J et al (2004). Evaluation of urine sucrose concentration for detection of gastric ulcers in horses, Am J Vet Res 65(1): 31-39. Sangiah, MacAllister C C and Amouzadeh H R (1989). Effects of misoprostol and omeprazol on basal gastric pH and free acid content in horses, Res Vet Sci 47(3): 350-354. Sykes B (2013). Administration of once daily trimethoprimsulphadimidine does not improve healing of glandular gastric ulceration in horses receiving omeprazole: a blinded, randomised , Proc ACVIM Forum, Seattle, WA: 246. Venner M, Lauffs S and Deegen E (1999). Treatment of gastric lesions in horses with pectin- lecithin complex, Equine Vet J Suppl 29: 91-96.

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Figure 1. Gastric ulcers present in the squamous mucosa at the greater curvature (1a) and the lesser curvature (1b). 1c shows diphtheritic lesions in the glandular mucosa close to the pylorus.

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Figure 2. Large gastric lesion following sucralfate treatment showing adherent white gel.

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Figure 3. Stomach of a non-fasted horse demonstrating the solid mass of bicarbonate saliva- buffered ingesta adjacent to the squamous area.

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Figure 4. Stomach of a horse following withholding feed demonstrating fluid and acidic gastric contents with potential movement of the acidic fluid and contact with the poorly defended upper squamous mucosa.

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