jessica gaskins, pharmd clinical veterinary...

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


Katz. 2010 Gray S. 2010


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


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


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



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




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

http://www.thomsonhc.com.ezproxy.musc.edu/

http://www.thomsonhc.com.ezproxy.musc.edu/

Gigi Davidson

Dr. Wayne Weart

Dr. Alison Reif

Patti Andrews

Thank You

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