Does ranitidine administration improve gastrointestinal hypomotility in dogs?

a Knowledge Summary by

Lara Brunori DVM CertAVP(ECC) MRCVS ^1*

¹VetsNow 24/7 Pet Emergency Hospital, 123–145 North Street, Glasgow, G3 7DA
^*Corresponding Author (lara.brunori@gmail.com)

Clinical scenario

You are presented with a 3-year-old mixed breed female neutered dog diagnosed with postsurgical GI hypomotility on ultrasound. You wonder if the administration of ranitidine will be helpful in improving your patient’s GI motility.

The evidence

The evidence currently available on the use of ranitidine as a prokinetic agent pertains, for the vast majority, to experimental settings. Five single centred experimental non-randomised non-blinded crossover studies (Fioramonti et al., 1984; Bertaccini et al., 1985; Mizumoto et al., 1990; Kishibayashi et al., 1994; and Lidbury et al., 2012) investigated potential prokinetic properties of ranitidine both in vitro (Bertaccini et al., 1985; and Mizumoto et al., 1990) and/or in vivo on healthy conscious or anaesthetised dogs (Fioramonti et al., 1984; Bertaccini et al., 1985; Mizumoto et al., 1990; Kishibayashi et al., 1994; and Lidbury et al., 2012). Although four out of five studies (Fioramonti et al., 1984; Bertaccini et al., 1985; Mizumoto et al., 1990; and Kishibayashi et al., 1994) found some degree of gastrointestinal motility stimulation post-ranitidine administration, these results are difficult to compare and generalise due to the limited number of animals included in each study, different patient populations evaluated (conscious vs anaesthetised, starved vs non-starved), a variety of techniques employed to estimate GI motility and discordant dosing regimes or route of administration.

One single centred randomised non-blinded prospective controlled clinical trial (Favarato et al., 2012) investigated the effect of ranitidine on the incidence of post-anaesthetic regurgitation in dogs undergoing elective surgical procedures, however the results of this paper are hindered by a type II error due to a too small sample size and a low incidence of regurgitation episodes in this population.

Summary of the evidence

Appraisal, application and reflection

This summary stems from the need to look for further guidance in the treatment of a frequently encountered disorder in clinical practice. Dysmotility of the gastrointestinal (GI) tract, characterised by the inhibition of forward movement of ingesta, is a common cause of upper GI signs in dogs (Hall, 2008).

The physiological regulation of coordinated GI movements requires a complex interaction between multiple neurohumoral factors and the enteric nervous system (Whitehead et al., 2016). Any disruption to this finely tuned mechanism can result in oesophageal motility disturbances, delayed gastric emptying and functional ileus (Whitehead et al., 2016). A number of pathologies have been associated with GI hypomotility: infectious diseases (i.e. parvovirosis and ascarid infestation), inflammation of the GI tract (i.e. gastritis, enteritis, ulcers, and post-surgical gastroparesis), neoplasia with severe infiltrative processes (i.e. alimentary lymphoma), metabolic disturbances (i.e. hypokalaemia, hypoadrenocorticism, diabetes mellitus, uraemia), drug administration (i.e. opioids, adrenergic agonists and cholinergic antagonists) and acute stress with significant sympathetic stimulation (Hall, 2008).

Motor neurones located within the GI wall are usually excited by substances like acetylcholine, serotonin and substance P, while other signalling compounds like somatostatin, nitric oxide, catecholamines and gamma-ammino butyric acid tend to inhibit neuromuscular transmission (Whitehead et al., 2016).

The cornerstone of GI hypomotility treatment consists in the administration of agents promoting an excitatory response within the GI nervous system, these drugs are usually referred to as ‘prokinetics’.

The veterinary literature offers few reviews suggesting the use of a number of prokinetic drugs based on their mechanism of action (Hall & Washabau, 1999; and Whitehead et al., 2016).

Ranitidine is frequently mentioned in these reviews and it is often considered in practice for the treatment of dogs with GI hypomotility due to its acetylcholinesterase inhibitor effect (Hall & Washabau, 1999).

A thorough search has been performed using both CAB Abstract and Pubmed databases and applying multiple search word combinations.

The current available literature concerning ranitidine in dogs with upper GI disturbances is mainly focused on its H2-antagonist properties and gastroprotectant activity (Marks et al., 2018).

The few studies centred on its role as an acetylcholinesterase inhibitor and prokinetic have mainly been carried out in experimental settings and on healthy canine patients (Fioramonti et al., 1984; Bertaccini et al., 1985; Mizumoto et al., 1990; Kishibayashi et al., 1994; and Lidbury et al., 2012). Two studies included in vitro experiments (Bertaccini et al., 1995; and Mizumoto et al., 1990) and they both proved ranitidine to have consistent anticholinesterase properties. The same papers also showed a pro-kinetic effect in vivo at clinically relevant doses.  

Two in vivo only studies found ranitidine administered both orally and intravenously to have stimulatory effect on GI motility (Fioramonti et al., 1984; and Kishibayashi et al., 1994) however the doses administered in these papers were generally higher than the one currently indicated in clinical practice. Two more recent studies (Favarato et al., 2012; and Lidbury et al., 2012) investigating ranitidine administered at 2 mg/kg either orally or intravenously to healthy dogs who failed to show GI motility enhancement.

Overall, interpretation of the available evidence to draw clinical practice recommendations is significantly hindered by the fact that only healthy patients have so far been included. Furthermore, the populations considered are difficult to compare as some studies evaluated conscious patients and others anaesthetised patients as well as starved animals vs non-starved animals. These are all variables that in humans have been proven to modify GI motility (Luckey et al., 2003) as well as the GI tract response to prokinetic administration (Smout et al., 1985). On top of this there is also a significant variability, amongst the available literature, in the techniques employed to estimate GI motility, as well as discordant dosing regimes and route of administration.

In light of all the above, it is fair to conclude that ranitidine has shown effective prokinetic activity in vitro and in vivo when healthy experimental dogs have been evaluated, although often at dosages higher than the ones commonly recommended in clinical practice. Its efficacy in clinical scenarios with dogs presenting for hypomotility disorders, has yet to be evaluated. Further studies will be needed to try and support its rational use in canine patients with GI hypomotility.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts on the OVID interface – 1973 to 2020 Week 18 PubMed on NCBI interface – 1920 to May 2020
Search strategy:	CAB Abstracts: (dog or dogs or canine or canines or canis).mp. or exp dogs/ or exp canis/ (vomit* or emesis or anorexi* or inappetence or hyporexia or gastri* or gastroent* or gastrointestinal disorders or enteropat*).mp. or exp vomiting/ or exp anorexia/ or exp gastroenteritis/ or exp gastritis/ (ranitidine or H2-antagonist* or H2 antagonist* or H2 blocker or histaminergic antagonist* or acetylcholinesterase inhibitor or parasympathetic agent*).mp. 1 and 2 and 3 PubMed: (dog or dogs or canine or canines) (vomit or emesis or anorexia or inappetence or hyporexia or gastritis or gastroenteritis or gastrointestinal disorders or enteropathy) (ranitidine or H2-antagonist or H2 antagonist or H2 blocker or histaminergic antagonist or acetylcholinesterase inhibitor or parasympathetic agent) 4. 1 and 2 and 3
Dates searches performed:	14 May 2020

Exclusion / Inclusion Criteria
Exclusion:	Book chapters, clinical review articles, single case reports, articles not relevant to PICO, articles not available in English
Inclusion:	Articles available in English which were relevant to PICO

Search Outcome
Database	Number of results	Excluded – book chapters	Excluded – review articles	Excluded – single case reports	Excluded – not relevant to PICO	Excluded – full article not available	Excluded – not available in English	Total relevant papers
CAB Abstracts	57	3	2	1	48	1	1	1
PubMed	202	0	1	0	199	0	0	2
Additional papers*								3
Total relevant papers when duplicates removed								6

*Referenced by relevant papers or suggested by reviewers

The author declares no conflicts of interest.

Acknowledgement: Clare Boulton, Head of Library and Knowledge Services

1. Bertaccini, G., Coruzzi, G. & Poli, E. (1985). ‘Histamine H2 receptor antagonists may modify intestinal motility independently of their primary action on the H2 receptors’. Pharmacological Research Communications. 17(3), 241–254. DOI: https://doi.org/10.1016/0031-6989(85)90099-2
2. Favarato, E.S., Souza, M.V., Costa, P.R.S., Favarato, L.S.C., Nehme, R.C., Monteiro, B.S. & Bonfá, L.P. (2012). ‘Evaluation of metoclopramide and ranitidine on the prevention of gastroesophageal reflux episodes in anesthetized dogs’. Research in Veterinary Science. 93(1), 466–467. DOI: https://doi.org/10.1016/j.rvsc.2011.07.027
3. Fioramonti, J., Soldani, G., Honde, C. & Bueno, L. (1984). ‘Effects of ranitidine and oxmetidine on gastrointestinal motility in conscious dog’. Agents and Actions. 15(3–4):260–263. DOI: https://doi.org/10.1007/BF01972359
4. Hall, J.A. (2008). ‘Gastric motility disorders & prokinetic therapies in small animals’. Proceedings ACVIM Forum, San Antonio, Texas, USA, 4–7 June, 2008. Veterinary Proceedings. 670–672.
5. Hall, J.A. & Washabau, R.J. (1999). ’Diagnosis and treatment of gastric motility disorders.’ Veterinary Clinics of North America: Small Animal Practice. 29(2), 377–395. DOI: https://doi.org/10.1016/S0195-5616(99)50027-2
6. Kishibayashi, N., Tomaru, A., Ichikawa, S., Kitazawa, T. & Shuto, K. (1994). ‘Enhancement by KW-5092, a novel gastroprokinetic agent, of the gastrointestinal motor activity in dogs.’ Japanese Journal of Pharmacology. 65(2), 131–142. DOI: https://doi.org/10.1016/S0021-5198(19)35772-5
7. Lidbury, J.A., Suchodolski, J.S., Ivanek, R. & Steiner, J.M. (2012). ‘Assessment of the variation associated with repeated measurement of gastrointestinal transit times and assessment of the effect of oral ranitidine on gastrointestinal transit times using a wireless motility capsule system in dogs’. Veterinary Medicine International. 2012:Article ID 938417. DOI: https://doi.org/10.1155/2012/938417
8. Luckey, A., Livingston, E. & Taché, Y. (2003). ‘Mechanisms and Treatment of Postoperative Ileus’. Arch Surg. 138(2):206–14. DOI: https://doi.org/10.1001/archsurg.138.2.206
9. Marks, S.L., Kook, P.H., Papich, M.G., Tolbert, M.K. & Willard, M.D. (2018). ‘ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats.’ Journal of Veterinary Internal Medicine. 32(6), 1823–1840. DOI: https://doi.org/10.1111/jvim.15337
10. Mizumoto, A., Fujimura, M., Iwanaga, Y., Miyashita, N., Yoshida, N., Kondo, Y. & Itoh, Z. (1990). ‘Anticholinesterase activity of histamine H2-receptor antagonists in the dog; their possible role in gastric motor activity’. Neurogastroenterology and Motility. 2(4), 273–280. DOI: https://doi.org/10.1111/j.1365-2982.1990.tb00035.x
11. Smout, A.J., Bogaard, J.W., Grade, A.C., ten Thije, O.J., Akkermans, L.M. & Wittebol, P. (1985). ‘Effects of cisapride, a new gastrointestinal prokinetic substance, on interdigestive and postprandial motor activity of the distal oesophagus in man’. Gut. 26(3), 246–51. DOI: https://doi.org/10.1136/gut.26.3.246
12. Whitehead, K., Cortes, Y. & Eirmann, L. (2016). ’Gastrointestinal dysmotility disorders in critically ill dogs and cats’. Journal of Veterinary Emergency and Critical Care. 26(2), 234–253. DOI: https://doi.org/10.1111/vec.12449