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Home , Benzamide, Cisapride, Prucalopride, Tegaserod

VETTALK Volume 15, Number 04 American College of Veterinary Pharmacists

THE HARD TRUTH ABOUT PROKINETIC USE IN PETS Introduction Pathophysiology/Etiology to that observed in dogs. It can be The moving topic of this Vet Talk As with most diseases in the veteri- due to a trichobezoar, dehydration, newsletter will be prokinetic medica- nary world, the etiology and patho- obesity, old age, diabetes, immobility, tions. The availability of information physiology of are varied pain from trauma to the low back, on the many prokinetic agents is var- depending on the species being dis- bladder infection, or an anal sac infec- ied at best so an overall consensus of cussed, where in their gastrointestinal tion. In cases that are more chronic, prokinetic will be as- tract the problem is occurring, and underlying disease such as colitis or sessed in this article, hopefully giving any accompanying comorbid condi- (IBS) may better insight to practitioners about tions. be the culprit. On the other hand, the which agents to use in their patients. cause may be idiopathic which is Canines: In man’s best friend, consti- frustrating for both veterinarian and Prevalence pation has many origins. A dog’s patient since this form is most diffi- Chronic constipation and gastroin- digestive tract itself is complex but cult to treat. testinal stasis are highly debilitating ultimately the mass movements and conditions that not only affect human haustral contractions from the large Equines: Despite their large size, patients but our four legged patients intestine (colon), propel into the horses have incredibly delicate diges- as well! Though this condition is stimulating the internal anal tive systems. Their is rela- equally widespread amongst our nu- sphincter to relax. This then signals tively small compared to their body merous veterinary species, there are a the diaphragm and abdominal mus- size which then passes food through few specific groups who are more at cles to contract increasing pressure approximately 100 feet of digestive risk. For example, prevalence of con- while the external anal sphincter re- tract to include the small intestine, stipation is higher in the following laxes resulting in . How- then cecum, large colon, small colon, dog breeds: English Bulldogs, Boston ever, various factors can impede this and finally rectum. Terriers, and German Shepherds. multifaceted process. Such examples During times of illness or stress Cats who are most affected include include ingesting foreign objects (i.e. horses may stop eating, drinking, and Siamese, Domestic Shorthair, and socks, garden hoses, shoes), anal sac Manx as well as those cats who are inflammation, long term use middle-aged and male. Horses, rab- (i.e.), chemotherapeutic bits, guinea pigs, and chinchillas may medications (i.e.vincristine), obesity, also experience various forms of con- old age, immobility, and dehydration. stipation due to their unique digestive However, other more severe underly- systems. ing physiologic etiologies such as neuromuscular disease, diabetic gas- troparesis, or a neoplastic gastrointes- tinal obstruction may also be attribut- able to GI stasis.

Felines: Cats can also develop con- stipation from several causes as their process of defecation is fairly similar

with all of the aforementioned rea- Summary of Clinical Signs can develop colic which even in the sons, will surely result in a final out- 1. Increased tenesmus mildest form, results in pain, abnor- come of poor gastric motility 2. Failure to defecate mal motility, and even ileus. Colic 3. Fecal matter, if passed, is reduced has many origins but the forms most Rodents: Guinea pigs and chinchillas in quantity and is usually dry and likely to cause constipation are im- have a high metabolic rate, a hard paction colics due to fecal material, monogastric stomach, and an impres- 4. Presence of blood in stool parasites, or enteroliths. Other causes sive cecum that is so large it takes up 5. Feces that are particularly foul for gut immobility include pelvic approximately ½ of their body cavity. smelling flexure impaction from food, poor In the cecum, much like in horses and 6. May continuously get in and out food quality, an inability to access rabbits, there is fermentation by key of litter box without passing fecal free forage, dehydration, severe hind microflora. If their diets aren’t main- material limb pain or injury, or long term use tained appropriately with high fiber 7. Circling or pacing the stall with of medications such and low carbohydrates (similar to intermittent straining as . lagomorphs), dysbiosis occurs result- 8. Decreased activity and lethargy ing in GI distress. Other reasons for likely due to pain constipation include dehydration, old 9. Painful and/or bloated abdomen age, spinal pain, obesity, excess fatty 10. Decreased interest in food diet, a lack of exercise, and dental 11. Irritability disease than can severely impair eat- ing and drinking. Diagnosis The primary means of diagnosing Clinical Signs and Symptoms any species with gastrointestinal sta- The classical clinical sign of consti- sis is through a complete history, pation is straining to defecate without thorough physical exam, and careful production of feces, droppings, or observation of their patient’s behav- manure. Affected animals can be of ior. A CBC and Chemistry Panel will Lagomorphs: Rabbits and hares have either sex, although in cats there is a be useful for identifying and/or ruling digestive systems that resemble male predilection, and of any age out other disease processes such as horses, rather than dogs or cats. Per- though often younger or older ani- diabetes, pancreatitis, or an underly- haps it is for this reason that they too mals are most affected. Besides ing infection. Abdominal radio- are very prone to GI stasis. The tran- straining, there may also be signs of graphs and ultrasounds both present sit time of the small intestine is rapid, general discomfort, irritability, a de- the practitioner with an even better and fibrous material is quickly moved crease in appetite, and a frequent understanding to what is, or is not, to the cecum and large intestine. need to want to defecate with postur- palpated on physical exam. It is very The cecum is where fermentation by ing and lifted tail. Variations of these important to discuss with the owner bacteria occurs. Indigestible fibrous physical demonstrations will be spe- about being vigilant in observing particles then accumulate in the colon cies specific. These problems, if not their pet and noting any changes in and are rapidly transported to the rec- resolved, can become life threatening. their diet or daily bathroom habits tum for defecation, usually within 4 Chronic constipation causes severe then recording these and letting their hours of ingestion. However, a diet pain, endotoxemia, decreased blood veterinarian know as they make their low in fiber in turn results in low flow and eventual necrosis of the in- way through this process with their amounts of fiber in the colon and testinal tissue that if not medically pet. cecum which reduces the production managed aggressively, may lead to of volatile fatty acids, increases pH, surgery. Diagnostic Algorithm and destroys natural microflora. 1. Assess history, physical exam, A diet high in carbohydrates may and clinical signs result in clostridial overgrowth, while a. Auscultation of the abdomen excessive protein can cause increased b. Rectal exam and palpation ammonia which also results in dys- where appropriate biosis. Obesity, inactivity, spinal c. Perform oral exams on lago- trauma, trichobezoars, dehydration, morphs and rodents as this excess fruit or nuts, in combination could be affecting their die-

4. Urine analysis crease the water content of stool. It is tary intake 5. Abdominal Radiographs most often used in horses for treat- d. Determine from owners if pa- 6. Abdominal ultrasound ment of constipation and fecal impac- tient has ingested any foreign tions via a properly place nasogastric objects tube. Due to the detrimental risk of 2. Rule out iatrogenic disease aspiration, it is administered orally a. Current or past medications via a stomach tube at 10-50 ml per (oral, ophthalmic, otic, topical) dog every 12 hours, 10-25 ml per cat b. Exposure to possible house every 12 hours and 500-1000ml per hold toxins (plants, owner horse up to 2-4 liters daily. Rabbits medications, household may be given 1-2 ml per day for 3-5 cleansers) days. A dose for guinea pigs isn’t 3. Preliminary Lab Results Treatment established. For short term use this is a. CBC There are several options available a certainly an appropriate option but i. Identify a possible for veterinarians to treat constipation for chronic constipation, as soon as underlying infection and GI stasis in their patients, most of use ceases, constipation often b. Chemistry Profile which are focused on the underlying returns. This product is generally safe i. Serum chemistry disease such as giving fluids for dehy- in the hands of a practitioner with profiles may identify a dration or surgically removing an ob- minimal side effects of oily stool and comorbid disease state struction. We want to keep all our abdominal cramping. Despite being such as diabetes or renal animal patients well hydrated and OTC, this should never be recom- disease increase the fiber in their diets and mended for owners to give to their c. Urinalysis decrease the amount of carbohydrates. pets due to the deadly risk of aspira- i. Helpful to rule out a However, several of the most success- tion! possible urinary tract ful therapies for treatments of idio- infection as the source of pathic constipation (i.e., feline pain and straining ) have been removed from This is a disaccharide sugar con- 4. Radiographs the US market and are only available taining both fructose and galactose. It a. Confirm colonic distention through specialty veterinary pharma- creates a laxative effect by osmosis in with feces cies that compound. The choice of the colon as it is a non-absorbed sugar b. Identify an area of foreign therapy must be individualized to the that retains water in the intestine after body impaction, colonic afflicted species specifically and the oral administration. Side effects from masses, or even fracture exact type of gastric distress they are excessive use may cause fluid and 5. Abdominal Ultrasound experiencing as diagnosed by their electrolyte loss. Use with caution in a. Help identify the size and veterinarian. It is also critical to re- diabetic animals since it carries a risk internal architecture of area member pain control in the process of for hyperglycemia. The dose for dogs of GI stasis treatment. Ileus and chronic constipa- is 1 ml for every 4.5 kg every 8 hours. b. More detailed view of what tion are painful and it will be hard for The cat dose is 1 ml per 4.5 kg every is truly going on internally your patient to relax their abdomen to 8 hours by mouth. For horses, the without being invasive encourage normal bowel movements dose is 0.25-0.5 ml/kg per day by if they are tense with severe pain! mouth. In rabbits and rodents this Diagnostic Tests Surgical therapy, if warranted, can be isn’t recommended as the side effect In order to avoid surgery, medical helpful (i.e. horse with enterolith im- of severe can be detrimental treatment must be implicated as soon paction) but has significant risks, is to their overall health. as possible. Diagnostic testing should costly, and often times the underlying be performed to better understand cause must still be identified and cor- Gallimycin () which form of GI stasis the animal is rected. This macrolide antibiotic can be experiencing in order to treat and alle- given to “restart” the stomach during viate symptoms and improve quality acute episodes of gastric stasis in of life. This substance is a lubricant laxa- which oral intake is not tolerated. 1. Thorough history and physical tive and one of the most basic routes Erythromycin induces gastric propul- exam with rectal palpation of treatment with which to start. Min- sive contractions via stimulation of 2. CBC eral oil acts as a lubricant to help ease motilin receptors to increase smooth 3. Chemistry Panel the passage of fecal matter and in- muscle activity which then helps to tract. Ranitidine dosing for dogs is 2 megacolon (often in combination unload solid and non-digestible mate- mg/kg every 8 hours by mouth or IV. with lactulose and ) is 2.5 mg rials out of the stomach. It can also For cats, the dose is 2.5 mg/kg every by mouth for cats up to 10 pounds stimulate fundic contractility. The 12 hours IV or 3.5 mg/kg every 12 and if heavier than this, 5mg by intravenous formulations are erythro- hours by mouth. For horses, the dose mouth given every 8 to 12 hours 30 mycin gluceptate and lactate, but glu- is 6.6 mg/kg every 6 to 8 hours by minutes before food. For rabbits, ceptate is not currently available. The mouth or 2 m/kg every 6 to 8 hours guinea pigs, or chinchillas needing prokinetic dose, which is well below IV. In rabbits, the dose is 0.5 mg/kg assistance with motility, the dose is the antimicrobial dose, for dogs and every 24 hours IV or 2-5mg mg/kg by 0.1-0.5 mg/kg by mouth every 8 to 12 cats is 0.5-1 mg/kg every 8-12 hours mouth every 8 hours. The dose in hours. Though not used as fre- either by mouth or IV. In horses, the guinea pigs is also 2-5 mg/kg by quently, the dose in horses with ileus dose is 1 mg/kg IV. This medication mouth every 12 hours. Nizatidine is 0.1-0.25 mg/kg IV over 60 minutes may NOT be given orally to rabbits, dosing is only available for dog and or 0.1mg/kg IM injection with fre- guinea pigs, or other rodents. IV use cat species at 5 mg/kg by mouth every quency not noted. Side effects in vet- is generally not recommended either 24 hours and 2-5 mg/kg by mouth erinary patients appear minimal but as this route of administration is very every 24 hours respectively. Side may include vomiting, diarrhea, and difficult to attain in this patient sub- effects are generally mild and noted at abdominal discomfort. set. Side effects include diarrhea higher doses but may include dizzi- (especially in horses), hyperthermia in ness, , diarrhea, and myalgia. Gastride () foals, and vomiting. Mosapride citrate is a selective ben- Propulsid () zamide peristaltic stimulating agent Zithromax (azithromycin) This medication is a non-selective that works as a selective 5-HT4 re- This is another macrolide antibiotic 5-HT4 receptor ceptor agonist to create prokinetic that has been used as an alternative to and a 5-HT3 . This gastrointestinal movements to allevi- the aforementioned erythromycin. drug is recognized for its ability to ate GI symptoms associated with gas- This medication doesn’t appear to promote GI motility via the 5-HT4 tritis. Unlike cisapride that works have the drug-drug interactions seen receptor in the mysenteric plexus of throughout the entire gut, mosapride with erythromycin and is also associ- the digestive tract and by increasing only works on the stomach and small ated with less QT prolongation. release from nerve end- intestines (i.e. upper GI tract). In However, there are limited studies for ings. It is most often associated with dogs, one study recommended a dose its use in the treatment of delayed success in cats with IBS. However, of 2 mg/kg by mouth every 24 hours. gastric emptying. There is also con- due to an association with cardiac This study did not find any side ef- cerned for its higher cost and using it and death in humans, it is fects or changes in blood levels. The for gastric emptying instead of for currently not on the market and the feline dose is 5 mg by mouth every 12 antimicrobial treatment of an actual only makers in India have recently hours again with no side effects infection that may eventually create moved to cease production. The ori- noted. In horses, the gastric emptying the potential for antibiotic resistance. gin of this medication’s deadly car- dose is 0.5 mg/kg while the dose for Side effects include vomiting and di- diac profile in people has been iso- promoting cecal movement is 1.5-2 arrhea though it is better tolerated lated to the blockade of potent a hu- mg/kg orally every 12 to 24 hours. than erythromycin. There are no es- man Ether-a-go-go gene (hERG) The only side effect noted in these tablished doses for azithromycin as a channel which happens to be respon- dosing trials was one case of mild prokinetic in animals at the time of sible for the repolarization phase of depression. The dose in rabbits and this publishing. the cardiac action potential. Blockade guinea pigs, appears to be in a range of this hERG channel then increases of 0.1-1 mg/kg every 8 to twelve Zantac (ranitidine) & Axid the action potential phase via delay of hours. This product is not currently (nizaditine) the repolarization phase. Because this available in the U.S. but does come in Both of these medications are hista- gene is very human specific, perhaps 2.5 mg and 5 mg tablets. mine receptor antagonists aka “H2 this is why the cardiac profile in our blockers.” However, they are unique veterinary population appears safer Resolor () from others in their class in that they and with less cardiovascular compli- This medication is a ago- have the ability to improve gastroin- cations. The dose for dogs as a pro- nist with selective affinity for 5-HT4 testinal stasis via their prokinetic cho- motility agent is 0.1-0.5 mg/kg by receptors. In human clinical trials pru- linergic properties that improve gas- mouth every 8 to 12 hours 30 minutes calopride, at 2mg and 4mg, provided tric emptying into the proximal GI before meals. The dose for cats with daily accelerated whole gut, gastric, guinea pigs, 0.5 mg/kg is traditionally IM or SC injection or 4 mg SC every small bowel and colonic transit times used. 6 hours. Due to the vast array of GI in constipated patients. The dose of side effects, this medication is not prucalopride can be titrated up based Urecholine() recommended for rabbits or rodents. on clinical response. Side effects in This medication is considered a These side effects include bradycar- these studies collectively expressed cholinergic agonist normally used for dia, AV block, hypotension, convul- such adverse events as , nau- urinary retention since it stimulates sions, dizziness, drowsiness, weak- sea, or cramps and the parasympathetic nervous system ness, urticaria, diarrhea, muscle diarrhea. Cardiac toxicity does not to increase bladder muscle tone. cramps, nausea, salivation, stomach appear to be an issue at this point However, since it stimulates the para- cramps, vomiting, bronchospasm, likely because it does not appear to sympathetic nervous system as a dyspnea, increased bronchial secre- interact with either the hERG potas- whole, bethanechol not only increases tions and lacrimation. sium channel linked with cisapride bladder muscle tone but also stimu- arrhythmias, nor the 5HT1B receptors lates gastric motility, increases gastric where created problems. tone and possibly helps to restore This medication is a an- Prucalopride is available in Europe peristalsis. The dose for dogs is tagonist gastrointestinal agent and is and Canada, but not in the United 2.5mg to 15 mg (depending on size of not currently approved by the FDA in States therefore doses are not avail- dog) every 8 hours by mouth. Cat the USA but is available in Canada able at this time of publishing. dosing is 1.25-5mg per cat every 8 and other countries. There is cur- hours by mouth. Horses use a dose of rently an Investigation New Drug Ap- Reglan () 0.025 mg/kg SQ. Doses are not pro- plication at domperi- This medication is an vided for lagomorphs and rodents as [email protected]. It works by and prokinetic benzamide that acts as side effects restrict their use. These stimulating the motility of the upper a (D2) and at possible side effects may include hy- GI tract likely via dopaminergic ef- higher doses, a serotonin agonist at potension, tachycardia, abdominal fects and by increasing acetylcholine 5HT4. Interestingly, it also antago- cramps, diarrhea, nausea, vomiting, effects. The action of domperidone is nizes serotonin receptor 5HT3. Meto- salivation, lacrimation, and bronchial to inhibit dopamine receptors, en- clopramide ultimately enhances the constriction. hance the action of acetylcholine in response to acetylcholine in the upper the GI tract, increase gastric motility, GI tract tissue which enhances motil- and increase peristalsis to enhance ity and accelerates gastric emptying gastroduodenal coordination in order time. It also increases lower esophag- to facilitate gastric emptying and eal sphincter tone. However, since it speeding up small bowel transit time. crosses the CNS, restlessness coupled Overall, the efficacy of domperidone with depression and extrapyramidal in the presence of diabetic gastropare- side effects, keep the use of this drug sis appears to be similar to that of me- limited and the lowest effective dose toclopramide. However, unlike meto- for each patient should be used. A clopramide, domperidone doesn’t liquid formulation, as opposed to IV, Prostigmin(neostigmine) cross the blood brain barrier so it may allow for improved efficacy cou- This medication is an acetylcholi- doesn’t tend to cause the CNS effects pled with a lower dose since it may nesterase inhibitor that is usually used noted with metoclopramide. Though work better when it directly contacts as an antidote for anticholinergic in- not commonly used in dogs and cats the stomach. The dose commonly toxication and for treatment of myas- for constipation, reference doses were used in dogs and cats is 0.2-0.5 mg/kg thenia gravis and for urinary reten- 0.05-0.1 mg/kg by mouth every 12 to every 6 to 8 hours IV, IM, or by tion. However, it also has limited 24 hours. The dose in horses is 0.2 mouth. For horses, commonly a con- evidence for stimulating intestinal mg/kg given IV in order to promote tinuous IV infusion is used at 0.125- motility. The following doses for gastric and small intestinal motility. 0.25 mg/kg/hour in order to reduce dogs and cats are based on the treat- The dose for rabbits is 0.5 mg/kg by postoperative ileus. In rabbits the ment for urinary retention which is 2 mouth every 12 hours. Side effects dose is 0.5 mg/kg every 6 to 8 hours mg/kg per animal per day often given that may be noted include xerostomia, by mouth or SC injection. The dose in divided doses such as every 12 dizziness, and tachycardia. commonly used in rodents is 0.2-1.0 hours. In horses for prevention of Amitiza () mg/kg every 12 hours by mouth, IM cecal and large colon impactions the This medication is a bicyclic fatty injection, or SC injection although in dose is 0.0044-0.022mg/kg via IV, acid that acts locally at the apical por- ing, since it is a newer therapy, it has be able to give once or twice daily tion of the intestine as a chloride been included for sake of complete- dosing. In this way, we can work channel activator, increasing intesti- ness. closely with the referring veterinarian nal fluid secretion and intestinal mo- to make sure drug therapy chosen fits tility. It is FDA approved for treat- Prognosis both treatment and owner demands. ment of chronic idiopathic constipa- Once present, motility problems may Being supportive and counseling on tion and constipation associated with or may not continue to be a lifetime the various forms of constipation and irritable bowel syndrome in humans. problem depending on what is the gastric stasis medications currently While it is only approved in humans underlying cause. It is very important managing their situation to the best of and no studies have currently been to increase your patient’s hydration our ability is critical in earning and conducted in cats, dogs or horses, whether this is through wet food for keeping our owners trust! there was a pilot study that proved its dogs and cats, adding salt to horses efficacy in reversing opioid induced diets to increase their natural thirst constipation in guinea pigs. Side ef- response, and providing a salt wheel fects include headache, nausea, diar- for your rabbit and rodents for the rhea, flatulence, abdominal pain, and same reasons. It is also key to in- dizziness. Interestingly it does not crease the fiber in their diets and keep appear to alter sodium or potassium the carbohydrate ratio on the lower concentrations in the blood. With the side. Hay quality for horses, rabbits, lack of available products to treat and rodents is very important for their chronically constipated patients, it is digestive health. No matter what the being included for sake of complete- species or their size, good attentive ness. husbandry is key to overall treatment success. This is currently an investigational Role of Veterinary Pharmacist *Further Reading Upon Request drug that acts as a peptide agonist of Treating pets with motility and gas- guanylate cyclase-C receptor. It is troparetic issues offers a plethora of minimally absorbed and via this re- unique opportunities for veterinary ceptor, it stimulates secretion of intes- pharmacists as many of these prod- tinal fluid and in theory, increases ucts must be compounded because transit time. Two large human trials they are simply not commercially showed an improvement in bowel available nor in a dosage form accept- movement from baseline and the final able to our patients. Such examples FDA review and approval should be include cisapride capsules, bethan- completed by September 2012. The echol for injection, domperidone cap- most common and dose-related ad- sules, and lower volume and flavored verse event was diarrhea. Since this H2 blockers for our smaller patients. is a new product, the appropriate ani- In addition to making compounded mal doses and long-term risks of medications, we also need to provide treating chronic constipation with this proper counseling on how to adminis- This article was submitted by: drug remain unknown. ter these medications and what side Jessica Gaskins, PharmD effects to look for. Owners may be a North Carolina State University Botulinum toxin little uncomfortable or even queasy College of Veterinary Medicine Botulinum toxin when injected into about discussing their animal’s diges- Veterinary Pharmacy Resident the pylorus has been proposed to im- tive disorders so we must do our best prove gastric emptying and associated to make them comfortable and famil- symptoms. However, a controlled iarize them with these drugs used to trial in humans found no significant alleviate their pet’s uncomfortable difference in gastric emptying or symptoms. Cost is another area we symptoms when compared with pla- must consider. Perhaps lactulose and cebo at one month. On the other ranitidine are all they can manage. It hand, there were no serious side ef- is also important to consider dosing fects. Despite a lack of animal dos- intervals; owners that work may only