Jessica Gaskins, PharmD
Clinical Veterinary Pharmacy Resident
North Carolina State University
College of Veterinary Medicine
Describe digestion and gastric ulcers in equines
Define mechanism of action of GastroGard®(omeprazole)
Describe role of calcium in equine physiology
Discuss omeprazole and calcium retrospective analysis of NCSU CVM horses
Discuss clinical implications of proton pump inhibitor use
Objectives
Digestion: A Delicate Factory
Despite their large size, horses have very sensitive digestive tracts
Equisearch.2010.Equisearch.com
Mouth 3 salivary glands
Contain bicarbonate and amylase
Esophagus Little to no reflux ability
Stomach Only holds 8-16 quarts with 3 primary components Saccus caecus
Fundic region
Pyloric region
How the Factory Runs
The Horse.2006. Thehorse.com
Small Intestine
Enzymatic digestion
Primary absorption of Ca2+
Large Intestine
5 compartments (cecum, large colon, small colon, rectum, anus)
Cecum has many specific microbes that create fermentation for remainder of undigested products
How the Factory Runs
The Horse.2006.Thehorse.com
Upset to this delicate system has several causes:
Stress
Exercise
NSAIDs
Improper feeding
Result:
Non-glandular and glandular ulcers
Equines and Ulcers
Mark Johnston racing, 2010. markjohnston.webalistic.co.uk
Stress
Illness
Stabling
Trailering
Showing
Weaning
Mechanism of action not definitive
Inflammation or ∆ in mucosal QH
Equines and Ulcers
iNetGiant, 2011. arkansas.inetgiant.co NationwideHorseTransportation, 2011.
Murrary, 2002. StockHorse, 2009. stockhorseshowhorse.com
Exercise
Dressage, endurance, eventing, polo, reining, racing
Movement increases acid exposure to the squamous mucosa area by raising the level of
liquid gastric contents
Equines and Ulcers
Horses Planet, 2009. horsesplanet.com
BBC Sport, 2007. newsimg.bbc.co.uk
NSAIDs are non-steroidal anti-inflammatory drugs that
inhibit cyclooxygenase which allows them to act as
Analgesics
Antipyretics
Anti-inflammatories
Examples
Phenylbutazone
Flunixin meglumine
Ketoprofen
Equines and Ulcers
Mechanism of Action: NSAID
Journal on the web.1998. journals.prous.com
NSAIDs block COX-1 and COX-2
COX-1 inhibition “Housekeeping” enzyme
Decrease mucous layer and bicarb
Inhibit renal blood flow
Impair mucosal lining repair
COX-2 inhibition Constitutively expressed enzyme
Block pain
Block inflammation
Mechanism of Action: NSAID
Improper Feeding
Large meal once daily
Equine stomach is designed to work best when ¾ full and have small meals often
No pasture turnout
Nature intended grazing to select most digestible grasses
Continuous flow of saliva buffers stomach acid
Primarily concentrates
Gut is designed for roughage intake
Carbohydrates ferment creating volatile fatty acids (VFA)
Equines and Ulcers
End Result
Non-glandular and glandular ulcers
Performance, appetite, and behavior affected
Strong acids attack unprotected squamous cells of saccus caecus non-glandular region
Equines and Ulcers
BritishVeterinaryAssociation. 2011. Inpracticebmj.com
Numbers to note
25% to 50% of non-competing horses have ulcers
93% of Thoroughbred racehorses have ulcers
75% to 90% develop glandular ulcers on an NSAID
Equines and Ulcers
Mubridge. 2009.timpickup.wordpress.com
Vet Clin Equine. 2009
Ulcers cause the following symptoms…
Weight loss
Irritability
Chronic colic
Lethargy
Anorexia
Poor coat condition
Equines and Ulcers
Start an Animal Sanctuary; 2010. startananimalsanctuary.com
Treatments
Histamine-2 antagonist (H2 Blocker) Ranitidine, famotidine, cimetidine Only block existing acid Short acting, needs frequent dosing (TID) Drug interactions
Gastric Mucosal Protectant Sucralfate (sucrose octasulfate + aluminum hydroxide) Forms complex with positively charged proteins creating viscous adhesive paste protecting gastric lining against peptic acid, pepsin, and bile salts Drug interactions Short acting, needs frequent dosing (TID)
Proton Pump Inhibitor (PPI) Omeprazole, lansoprazole, pantoprazole Blocks and prevents acid from forming in ~3 days Helps heal ulcers and prevent future ones Irreversible, longer acting (SID) Drug Interactions
Gastric Ulcers
Drug Class Proton Pump Inhibitor (PPI)
Substituted benzimidazole
Mechanism of Action Irreversibly/specifically inhibits parietal cell
hydrogen–potassium adenosinetriphosphatase enzyme system Proton pump of gastric mucosa is H +, K +-ATPase
Suppresses gastric basal and stimulated HCl secretion
Omeprazole
Omeprazole
Creative Commons. 2011. Creativecommons.org
Efficacy Maintains gastric pH ≥4 Must give 30 minutes PRIOR to morning meal
Established in many clinical trials 77% of omeprazole treated horses remained ulcer free while in race
training
Cost PPI>H2Blocker>Sucralfate
Safety Side effects are minimal Long term use? Studies in human population of ↓ calcium Newer studies examining risk for fractures
Treatment with Omeprazole
Murray, 2011 Ngamruengphong, 2011 Merial. 2009. F.O.I. Summary
Effect of gastric acid secretion on intestinal phosphate
and calcium absorption in normal subjects Nephrology Dialysis Transplantation, 1995
Non-randomized, placebo-controlled, cross-over clinical trial
Objectives: To determine if gastric pH truly affects calcium absorption
Methods: Normal subjects 24-h urinary calcium phosphate and postprandial blood calcium measured
Study: Following exclusion criteria, 8 subjects received 60mg omeprazole or placebo and 1 gram of calcium with each meal for 3 doses and then the washout period occurred and same procedure repeated
Results: Inhibition of gastric acid secretion by omeprazole significantly (p<0.05) reduces calcium in normal subjects
PPI use in Humans
Effects of proton pump inhibitors on calcium
carbonate absorption in women The American Journal of Medicine, 2005
Randomized, double-blind, placebo-controlled, cross-over clinical trial
Objective: To determine the role of PPI’s on pH in Calcium absorption
Methods: Volunteers ingest omeprazole 20mg or placebo q am x 7 days along with a Ca-labeled calcium carbonate capsule such that calcium concentrations can be measured by atomic absorption spectrophotometry with blood levels drawn at baseline and 5 hours post ingestion
Study: Following exclusion criteria, 18 subjects completed the trial to include 1 week treatment with 3 week wash out before using the other treatment for 1 week (drug vs. placebo)
Results: 1 week course of omeprazole 20mg daily significantly (p<0.05) decreased fractional calcium absorption under fasting conditions.
PPI use in Humans
O’Connell, 2005
PPI’s and Risk of Fracture: A Systematic Review
and Meta-Analysis of Observational Studies American Journal of Gastroenterology 2011
Systematic review of and meta-analysis of controlled observational studies to evaluate the risks of PPI use on fracture outcome
Objectives: Studies suggest gastric suppression could result in decreased intestinal calcium absorption and subsequent bone fractures. Evaluating these risks via review and meta-analysis in hope of a conclusion.
Methods: All controlled observation studies that compared fracture outcome in patients with PPI therapy with a control group were included. Pooled odds ratios (ORs) were calculated with 95% confidence interval via random-effects model.
Results: 1,668 studies used and 10 (4 cohort and 6 case controlled) found 223,210 fractures included in analysis. There was significant statistical and clinical heterogeneity among studies and found a modest association between PPI use and increase risk of hip and vertebral fractures.
PPI use in Humans
Gastric acid suppression associated with an ↑ risk of
Community-acquired pneumonia
Clostridium difficile infection
Risk of a fracture ↑with duration of treatment of PPI
High doses for > 1 year- hip fracture
Standard doses <3 years- spine, forearm, wrist fractures
Decrease in stomach acid ↓ionized calcium in stomach
Interfere with absorption in SI
Omeprazole may interfere with osteoclasts
Bone matrix density ↑ but bone remains brittle inside
PPIs and Human Safety
Katz. 2010 Gray S. 2010
The FDA is revising Rx and OTC labels for PPIs Possible ↑risk of fractures (hip, wrist, spine) Based upon FDA review of long-term studies
Osteoporotic fracture associated with increased Cost Morbidity Mortality
Other contributing factors Diabetes Obesity Osteoporosis Fracture history Smoking
PPIs and Human Safety
Katz. 2010 Gray S. 2010
PPIs and Human Safety
FDA Drug Safety Communication: Possible
increased risk of fractures of the hip, wrist, and
spine with the use of proton pump inhibitors
Update: 3/23/2011
Safety Announcement
[05-25-2010] The U.S. Food and Drug Administration (FDA) is revising the prescription and over-the-
counter (OTC) labels for a class of drugs called proton pump inhibitors to include new safety information
about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.
The new safety information is based on FDA's review of several epidemiological studies that reported an
increased risk of fractures of the hip, wrist, and spine with proton pump inhibitor use. Some studies found
that those at greatest risk for these fractures received high doses of proton pump inhibitors or used them
for one year or more.The majority of the studies evaluated individuals 50 years of age or older and the
increased risk of fracture primarily was observed in this age group.
Healthcare professionals and users of proton pump inhibitors: OTC PPIs are marketed at low
doses are only intended for a 14 day course of treatment up to 3 times per year. Healthcare
professionals should be aware of the risk for fracture if they are recommending use of OTC PPIs at
higher doses or for longer periods of time than in the OTC PPI label.
99% of calcium is in the bone
Remaining 1% in extracellular fluid
40% Protein bound
50% Ionized as Ca2+
10% Complexed with anions
Bicarbonate, citrate, lactate, phosphate
Adult horses need 40mg/kg/day
Growing horses need 50-75g/day
Calcium Absorption
Reed, 2010 Toribio, 2009
Crude Protein (min.) 12.00% Lysine (min.) 0.60% Methionine (min.) 0.20% Threonine (min.) 0.40% Crude Fat (min.) 12.00% Crude Fiber (max.) 15.00% Calcium (min.) 0.75% Calcium (max.) 1.25% Phosphorus (min.) 0.45% Magnesium (min.) 0.40% Iron (min.) 250 ppm Potassium (min.) 0.90% Selenium (min.) 0.50 ppm Zinc (min.) 160 ppm Manganese (min.) 100 ppm Copper (min.) 50 ppm Vitamin A (min.) 5,500 IU/lb Vitamin D (min.) 750 IU/lb Vitamin E (min.) 150 IU/lb Ascorbic Acid (min.) 40 mg/lb Biotin 0.25 mg/lb Lactobacillus Acidophilus Fermentation Product (min.)
1.4 million CFU/gm
Saccharomyces Cerevisiae Yeast Culture (min.)
2.80 million CFU/gm
Cellulase (Trichoderma Longibrachiatum Fermentation Extract (min.)
125 CMC–ase Units/lb
Protease (Bacillus Subtilis Fermentation Extract (min.)
0.40 Northrup Units/lb
Calcium Example
Guaranteed Analysis
Shredded Beet Pulp, Cane Molasses, Whole Oats, Soybean Oil, Dehulled Soybean Meal, Wheat Middlings, Alfalfa Meal, Soybean Hulls, Distillers Dried Grains, Ground Limestone, Monocalcium Phosphate, Dicalcium Phosphate, Defluorinated Phosphate, Salt, Magnesium Oxide, Hydrolyzed Yeast, Zinc Proteinate, Copper Proteinate, Manganese Proteinate, Kelp Meal, Yeast Culture, Hydrated
, Anethole, Fenugreek Seed, Lecithin, Iron Proteinate, Magnesium Proteinate, Dried Trichoderma Longibrachiatum Fermentation Extract,
, Selenium Yeast, Dried Lactobacillus Acidophilus Fermentation Product, Dried Enterococcus Faecium Fermentation Product, Dried Bacillus Subtilis Fermentation Extract, Stabilized Rice Bran, Vitamin E Supplement, Flaxseed, Ascorbic Acid (Source of Vitamin C), Niacin Supplement, Biotin, Vitamin A Supplement, Thiamine Mononitrate, Beta Carotene,
Riboflavin Supplement, Pyridoxine Hydrochloride, Vitamin B12 Supplement, Vitamin D3 Supplement, Choline Chloride, Menadione Sodium Bisulfite Complex, Folic Acid, Sodium Bicarbonate, Sodium Sesquicarbonate, Ferrous Sulfate, Zinc Sulfate, Manganese Sulfate, Copper Sulfate, Cobalt Sulfate, Ethylenediamine Dihydroiodide, Brewers Dried Yeast, Monosodium Phosphate, L-Lysine, Lignin Sulfonate, DL-methionine Hydroxy Analog, DL-methionine, Propionic Acid, Sodium Benzoate, Potassium Sorbate.
Ingredients
Insoluble and Soluble Calcium Carbonate-insoluble
Most common
Low pH required for proper absorption in the intestine
Calcium carbonate is 40% elemental calcium 1000 mg will provide 400 mg of calcium
Calcium Citrate-soluble
Uncommon in horse feeds
Choice for individuals taking H2Blockers or PPIs
More easily digested and absorbed than calcium carbonate
Calcium citrate is about 21% elemental calcium 1000 mg will provide 210 mg of calcium
Calcium Absorption
Dipiro J. 2009
Stomach pH~2
Calcium absorbed in ionized form via acidic medium (HCl) releasing calcium from salt or food complex
Omeprazole blocks acid
Calcium not becoming ionized therefore questionable ability to be absorbed in small intestine
GastroGard© correlation Calcium homeostasis
Low levels equal impaired bone deposition
Low levels stimulate PTH ↑bone resorption
Calcium Absorption
Surveyed admitted CVM horses from 2009-2011 Groups were: ≤6 months, 7 months to 24 months, >2 years to 14
years old, ≥15 years old Treatment naïve total serum calcium baselines to compare to PPI
treatment groups
Exclusions Taking omeprazole or H2 blocker Given calcium gluconate Bottle fed Pregnant Gastrointestinal disease: colic, diarrhea Abnormal albumin levels Death
Treatment-Naïve Calcium Data
27 met criteria in the ≤6 month old group
93% had total calcium level WNL (11.3-13.4mg/dl)
Fractures, eye injuries, lethargy, born at hospital
Mean calcium of 12 mg/dl
Treatment-Naïve Calcium Data
www.montanacowgirl.com
5 met criteria in the 7 month to 24 month old group
100% had total calcium WNL (11.3-13.4mg/dl)
Lameness, cryptorchid, eye injuries
Mean calcium of 12.3 mg/dl
Treatment-Naïve Calcium Data
www.breakthroughdressage.com
70 met criteria in the >2 years old to 14 year old group
92% had total calcium level WNL (11.3-13.4 mg/dl)
Lacerations, eye injuries, lameness, castration
Mean calcium of 12.1 mg/dl
Treatment-Naïve Calcium Data
www.generationsegyptianarabians.com
37 met criteria in the ≥15 years old group
87% had total calcium level WNL (11.3-13.4 mg/dl)
Ophthalmology issues, lesions, lameness, choke, wounds
Mean calcium of 12.4 mg/dl
Treatment-Naïve Calcium Data
Treatment-Naïve Calcium Data
Age Mean Calcium 1o Breed Reported Age Significance
< 6 months 12 mg/dl Quarter Horse Most ≤ 3 months
7 months to 24 months
12.3 mg/dl Quarter Horse Most ~2 years old
>2 years old to 14 years old
12.1 mg/dl Arabian and
Quarter Horse NA
≥ 15 years old 12.4 mg/dl Thoroughbred and
Quarter Horse Most >20 years
NCSU CVM admitted horses from 2009-2011 analyzed
Exclusions Total serum calcium levels before and after PPI not measured Gastrointestinal diseases: colic, diarrhea Given calcium gluconate Bottle fed Pregnant Abnormal serum albumin levels
Inclusions All breeds All ages Taking treatment dose of omeprazole
Total of 30 met criteria Analyzed ↓total serum calcium levels after omeprazole treatment
20 horses experienced a decrease
Omeprazole-Exposed Calcium Data
Total population that experienced ↓ calcium
67%
Analyzed via ANOVA and ∆ in Ca2+ found to be statistically significant (p<0.0125)
Subpopulation with decrease
45% were 2 years old or younger
Age group where calcium availability is critical
Omeprazole-Exposed Calcium Demographics
Redbubble,2011.redbubble.com MJMillerRanch, 2007. Prancingpixels.com
Omeprazole Subgroup Demographics
Population Quarter Horse
Thoroughbred Appaloosa Paint Saddlebred Arabian Walking
Horse
Standardbred Total
(n=20)
Age <6 months
3 1 1 5
Age 7months-24months
1 1 1 1 4
Age > 2years to 14 years
2 4 2 1 9
Age ≥15 years 1 1 2
Age Population Mean
Duration of Treatment
Mean Ca2+ before PPI
Mean Ca2+ after PPI
Statistically Significant
(p<0.05)
Clinically Significant
Foals (≤6 months)
n=5 7 days 12.8 10.8 0.002 Likely
Weanlings/Yearlings (7 months-24 months)
n=4 15 days 12.8 11.3 0.098 Perhaps
Adolescents/Adults (>2-14 years)
n=9 13 days 12.4 11.7 0.007 Not likely
Seniors/Geriatrics (≥15 years)
n=2 17 days 12.9 11.5 0.257 Not likely
Omeprazole Subgroup Data Analysis
YourHorse. 2009. Yourhorse.co.uk
Omeprazole Subgroup Data Analysis
Age Population Mean Duration of Treatment
Mean Ca2+ before PPI
Mean Ca2+ after PPI
Statistically Significant
(p<0.05)
Clinically Significant
0-24 months
n=9 10 days 12.8 11 0.0078 Likely
>24 months
n=11 11 days 12.5 11.6 0.0016 Not likely
0 months through 30 years
n=20 12.5 days 12.6 11.3 0.0001 Perhaps
YourHorse. 2009. Yourhorse.co.uk
Lesser of 2 evils Painful gastric ulcers
Delay career
Decrease quality of life
Chance for fracture or developmental orthopedic disease (DOD)
Delay career
Decrease quality of life
Treatment Risks vs. Benefits
Seriousness of disease vs. Seriousness of adverse effects
Current Therapy
8 week old foal needs gastric ulcer treatment so you…
Treat with omeprazole 4mg/kg
Treat with omeprazole 2mg/kg
Treat with omeprazole 4mg/kg and sucralfate
Treat with ranitidine and sucralfate
Don’t treat and let nature run its course
Clinical Implications
Prospective, treatment randomized, placebo controlled trial with oral
omeprazole to observe affects on blood calcium levels Methods: Omeprazole 4mg/kg dose or placebo administered once
daily for up to 3 weeks duration in healthy young horses Populations: ≤12 months and 13 months-24 months
Control and treatment groups for each Power calculations for group size undetermined
Inclusion criteria: Appropriate age, UTD on vaccines, no weight, gender or breed restrictions
Exclusion criteria: Previous PPI /H2 treatment, history of colic, bottle fed, abnormal albumin or phosphate levels
Study: Obtain baseline and treatment serum calcium levels at 1 week, 2 weeks, and 3 weeks for each age group
Results: Determine if gathered values are statistically and (or) clinically relevant in each age group
Future Investigation
Katz M. 2010
http://www.thomsonhc.com.ezproxy.musc.edu. Micromedex 2.0. August 3rd. Omeprazole.
Luthersson N, Nielsen KH, Harris P, et al. The prevalence and anatomical distribution of equine gastric ulceration syndrome (EGUS) in 201 horses in Denmark. Equine Vet J. 2009 Sep;41(7):619-24.
Videla R, Andrews FM. New perspectives in equine gastric ulcer syndrome. Vet Clin North Am Equine Pract. 2009 Aug;25(2):283-301.
Reed S, Bayly W, and Sellon D. Equine Internal Medicine. 3rd Edition. Saunders, 2010.
Toribio R. Disorders of Calcium and Phosphate Metabolism in Horses. Vet Clin Equine. 2011; 27: 129-147.
Nieto J, Spier S, Pipers F, et al. Comparison of paste and suspension formulations of omeprazole in the healing of gastric ulcers in racehorses in active training. JAVAMA. 2002 October; 221(8): 1139-1143.
Freedom of Information Summary. GastroGard(omeprazole). Merial Limited. Iselin, New Jersey. 2001.
White G, McClure S, Sifferman R, et al. Effects of short term light to heavy exercise on gastric ulcer development in horses and efficacy of omeprazole in paste in preventing gastric ulceration. JAVMA. 2007 June; 230(11): 1680-1682
Murray MJ, Grodinksy C, Anderson CW, et al. Gastric ulcers in horses: a comparison of endoscopic findings in horses with and without clinical signs. Equine Vet J Suppl. 1989; 7: 68-72
Toribio R, Kohn C, Chew D, et al. Comparison of serum parathyroid hormone and ionized calcium and magnesium concentrations and fractional urinary clearance of calcium and phosphorus in healthy horses and horses with entercolitis. AJVR. 2001 June; 62(6): 938-947.
Ngamruengphong S, Leontiadis G, Radhi S, et al. Proton pump Inhibitors and Risk of Fracture: A systematic Review and Meta-Analysis of Observational Studies. A J Gastroenterol. 2011; 106: 1209-1218.
Bodmer M, Meier C, Kraenzlin M, et al. Proton Pump Inhibitors and Fracture Risk. True effect of Residual Confounding. Drug Saf. 2010; 33(10): 843-852.
Ito T and Jensen R. Association of Long-Term Proton Pump Inhibitor Therapy with Bone Fractures and Effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium. Curr Gastroenterol Rep. 2010; 12: 448-457.
Murray MJ. Manual of Equine Gastroenterology. Ch. 12 Diseases of the Stomach. 2002. 241-248.
Murray MJ. Manual of Equine Gastroenterology. Ch. 23 Stomach Diseases of the Foal. 2002. 469-476.
Matthew J, Sullivan R, Stomberg E, et al. Inhibiting Gastric Acid Production Does Not Affect Intestinal Calcium Absorption in Young, Healthy Individuals: A Randomized, Crossover, Controlled Clinical Trial. JBMR. 2010; 25(10):2205-2211.
Katz, M. Failing the Acid Test. Benefits of Proton Pimp Inhibitors May Not Justify the Risks for Many Users. Arch Intern Med. 2010; 170(9): 7547-748
Gray S, LaCroix A, Larson J, et al. Proton Pump Inhibitor Use, Hip Fracture, and Change in Bone Mineral Density in Postmenopausal Women. Arch Intern Med. 2010; 170 (9): 765-771.
Lepeule J, Seegers H, Rondeaue V, et al. Risk factors for the presence and extent of Developmental Orthopaedic
Disease in the limbs of young horses: Insights from a count model. Preventive Veterinary Medicine. 2011; 101: 96-106.
Targownki L, Lix L, Metge C, et al. Use of Proton pump inhibitors and risk of osteoprosis-related fratures. CMAJ. 2008; 179 (4): 319-326
Richards J and Goltzman D. Proton pump inhibitors: balancing the benefits and potential fracture risks. CMAJ. 2008: 179 (4): 306-307
Schinke T, Schilling A, Baranowsky A, et al. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nature Medicine. 2009; 15(6): 674-681.
O’Connoll M, Madden D, Murray A, et al. Effects of proton pump inhibitors in calcium carbonate absorption in women: a randomized crossover trial. American J Med. 2005: 118: 778-781.
References
Gigi Davidson
Dr. Wayne Weart
Dr. Alison Reif
Patti Andrews
Thank You
Questions