EQUINE VETERINARY EDUCATION / AE / AUGUST 2019


443


pharmacological management of EGUS should be the optimisation of acid suppression therapy. Oral omeprazole remains the most commonly used medication and an understanding of the factors that affect its efficacy is important in tailoring treatment plans for affected individuals.


Diet Until recently the role of diet in the efficacy of oral omeprazole has been understated and the potential for feeding recommendations to potentially interact with drug efficacy largely ignored. Current recommendations include the provision of ad libitum roughage (Sykes et al. 2015a), which is logical given the dietary risk factors that have been identified for ESGD, but do not distinguish between recommendations during the therapeutic and preventative stages of disease management. In the author’s opinion, this is an error in clinical reasoning, and inconsistent with current evidence regarding the significant impact that feeding has on omeprazole absorption and efficacy. Ad libitum feeding, when compared with horses that


have had feed withheld overnight, reduces bioavailability, as measured by area-under-the-curve (AUC) of buffered formulations of omeprazole by approximately 50–66% (Daurio et al. 1999; Sykes et al. 2015c, 2017c). The primary determinant of efficacy of omeprazole in humans (Lind et al. 1983) and dogs (Abel€


o et al. 2000) is AUC, and, as such,


conditions that decrease AUC likely decrease the efficacy of omeprazole. Consistent with this, it has been shown that the magnitude and duration of acid suppression achieved in horses receiving an ad libitum hay diet is less than horses receiving a high grain/low fibre diet with an overnight fast and omeprazole administered 2 h prior to morning feeding (Sykes et al. 2017b). Equally important is that in the group receiving ad libitum hay minimal, if any, acid suppression was observed over a 5-day period in 3/6 animals even at a dose of 4 mg/kg bwt by mouth once daily (Sykes et al. 2017b). This suggests that under such conditions the current recommended doses are likely to be ineffective in some, if not many, animals when omeprazole is administered concurrently with ad libitum feeding. Considering this, the author suggests that current recommendations that do not distinguish between feeding management during treatment and prevention are inappropriate. Instead, the author proposes that the recommendations should be updated to include that, where possible, omeprazole be administered after an overnight fast. This small management change has significant potential to increase the efficacy of oral omeprazole in many patients. Once omeprazole treatment is completed, the current recommendation for ad libitum roughage as part of prevention management is appropriate as long as concurrent oral omeprazole therapy is not required for prevention.


Timing of feeding To date, little attention has been paid to the timing of feeding in regard to omeprazole administration and the impact of different meal feeding schedules has not been specifically studied. However, it is likely that the timing of feeding is important to the drug’sefficacy. Although horses are considered to be constant acid secretors, and the consistently low pH in the ventral stomach reflects this (Husted et al. 2008; Sykes et al. 2017b), there is also a significant


prandial effect and meal feeding increases plasma gastrin concentrations (Sandin et al. 1998). Proton pump inhibitors are prodrugs and require gastric acid secretion to be converted to their active form, and thus to inhibit acid secretion (in effect the proton pumps need to be turned on and producing acid to be inactivated and stop producing acid), and it is important the maximal stimulation of pumps occurs while drug concentrations are present (Shin and Sachs 2008). In the horse, the half-life of omeprazole is only approximately 30 min (Jenkins et al. 1992; Sykes et al. 2015d). Maximal serum concentration occurs at around 45–90 min (Sykes et al. 2015c,d, 2016, 2017c) and it is important that maximal stimulation occurs within this period. Further, the type of meal may be important as gastric distention appears to play a role in gastrin release in the horse. Larger amounts of gastrin are released more rapidly in response to voluminous, roughage-based meals when compared with smaller grain meals (Sandin et al. 1998). Considering this, the author recommends withholding of feed overnight, followed by the feeding of a large, roughage-based meal 60–90 min after administration of oral omeprazole, then any required grain/ supplement feeding.


Dose and individual variation Current dosing recommendations include blanket dose rates for treatment and prevention; however, these fail to take into account the wide range of individual dose responses that have been reported in the horse. When feed was withheld overnight, the bioavailability of an enteric-coated omeprazole formulation varied between approximately 5% and 50% in one study (Sykes et al. 2015d), and similar magnitudes of variation have been reported for buffered (Daurio et al. 1999; Sykes et al. 2016, 2017c) and plain (Sykes et al. 2015d) formulations. Given this wide variation, the use of a dose determined on average response means that some animals will be undertreated (potentially explaining the 15– 30% of ESGD nonresponders) and that some animals will be overtreated (wherein, a lower dose may improve compliance through increased affordability of the medication). In studies monitoring intragastric pH, the author has


consistently observed individual animals which fall into good, average and poor responder groups, regardless of the dose and conditions studied. To the author’s knowledge, there is no evidence in the horse that the magnitude and duration of acid suppression required for treatment differs from that required for prevention. Further, in monitoring intragastric pH levels, the author has repeatedly observed a threshold effect wherein a 50% reduction in dose does not equate to a 50% reduction in acid suppression. Instead, a threshold effect appears to be apparent where once a minimally effective dose is achieved for a specific individual under specific dietary conditions the effect goes from minimal to adequate acid suppression. Considering this, the author believes that individual responsiveness is likely a more important factor in tailoring the management of an individual animal, rather than blanket recommendations for treatment and prevention doses, as currently recommended (Sykes et al. 2015a). As such the author believes that dosing should be


considered on an individual level with the goal of finding the minimally effective dose for each individual animal under specific dietary conditions, rather than the current focus on treatment and prevention doses. In practice, the author uses


© 2018 EVJ Ltd


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88