This document is contained within the following "Collections" show

Antiemetics and Gastroprotective Drugs in Dogs: Fact and Fiction
WSAVA/FECAVA/BSAVA World Congress 2012
Thomas Spillmann, DMedVet, DrMedVet, DECVIM-CA
Professor of Small Animal Internal Medicine, Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland

Introduction

Vomiting or emesis is a self-defence mechanism but also a clinical sign of many gastrointestinal or extraintestinal diseases. Independent of the cause, severe or persistent vomiting can lead to a variety of pathological consequences. These include fluid and electrolyte deficits resulting in disturbed haemodynamics such as hypovolaemic shock, disturbances of the acid-base balance, and protein calorie malnutrition. The differentiation between cause and result of severe illness in vomiting patients is often not straightforward and leads to a time-consuming diagnostic work-up. Therefore, it is common to use antiemetics before the actual diagnosis is established and more directed treatment is possible. To improve the care for vomiting patients, the European Emesis Council has established guidelines for their effective diagnostic workup and medical (antiemetic) treatment.

In vomiting patients it is always anticipated that the gastric mucosa is primarily or secondarily affected by the underlying gastrointestinal or extraintestinal disease process. Therefore, antiementics are often combined with gastroprotective drugs. However, the current use of many antiemetics and gastroprotectives is based on data from human medicine, empirical evidence, pathophysiological justification and expert opinions.

Antiemetics

Antiemetics commonly advocated for use in dogs include phenothiazines and antagonists of dopamine, serotonin (5-HT3), and neurokinin-1 receptors.

Phenothiazines (e.g., chlorpromazine: 0.2–0.5 mg/kg i.m., s.c. q6–8h; acepromazine: 0.01–0.05 mg/kg i.m., 1–3 mg/kg orally) are sedatives with only centrally acting antiemetic effects on adrenergic, dopaminergic, histaminergic and cholinergic receptors in the vomiting centre, the chemoreceptor trigger zone (CRTZ) and the vestibular organ. It has been reported that chlorpromazine has less effect on cisplatin-induced vomiting in dogs than metoclopramide. It has the same effect as maropitant in preventing centrally (apomorphine) but not in peripherally induced (syrup of ipecac) vomiting. Acepromacine prevents opiate-induced vomiting when added to the preanaesthetic protocol. Considering that phenothiazines have hypotensive properties with detrimental effects on dehydrated patients and sedative effects which are dangerous for dogs with peripherally induced vomiting, their indication for treating vomiting is very narrow.

Dopamine receptor antagonists (e.g., metoclopramide: 0.2–0.4 mg/kg orally, s.c., i.m. q6–8h; 1–2 mg/ kg/24hrs constant-rate infusion (CRI)) have an effect on adrenergic and dopaminergic receptors in the CRTZ and the vomiting centre. In dogs, they also have prokinetic effects on the antrum, pylorus and duodenum. There is vast empirical evidence for their effect in toxic and centrally induced vomiting, and in improving gastric outflow. However, there is only one cross-over study in healthy dogs showing that the effect of metoclopramide equals the effect of maropitant in preventing centrally induced vomiting but that it is less effective for peripherally induced vomiting. One randomised, multicentre clinical trial revealed that giving metoclopramide 2–3 times/day is less effective than single maropitant application for treating vomiting dogs. However, the study does not differentiate between centrally and peripherally induced vomiting. Despite the lack of good evidence-based clinical studies, metoclopramide remains the main treatment option to address centrally, especially CRTZ, induced vomiting. For best effect in a vomiting patient, the possible underlying pathophysiology should be considered before using metoclopramide.

Serotonin (5-HT2) receptor antagonists (e.g., ondansetron: 0.5–1 mg/kg orally q12–24h; 0.5 mg/kg i.v. loading dose, followed by 0.5 mg/kg/hr over 6 hours) have an effect on serotinergic receptors in the gastrointestinal tract. One experimental study in dogs proved efficacy for ondansetron and lerisetron in radiation-induced vomiting. Ondansetron is as effective as maropitant in preventing peripherally induced vomiting but is less effective for centrally induced vomiting. Therefore, its main indications would be disorders causing peripherally induced vomiting (e.g., cisplatin chemotherapy, parvovirus infection). However, clinical studies about its efficacy in these conditions are not available.

Neurokinin-1 receptor antagonists (e.g., maropitant: 1 mg/kg s.c. q24h, 2 mg/kg orally q24h; travel sickness: 8 mg/kg orally, 2 hours before travel) affect not only NK1 receptors in the gastrointestinal tract, CRTZ, and vomiting centre but at high doses also prevent vestibular-induced travel sickness in dogs and cats. Several experimental and clinical studies have proven the efficacy of maropitant to prevent and treat both peripherally and centrally induced vomiting including travel sickness with very low risk of side effects. It may be an advantageous empirical drug to use in the vomiting patient due to the lack of effect on the underlying disease causing vomiting.

Gastroprotective Drugs

Gastroprotective drugs used in small animal medicine are antacids, inhibitors of acid production such as histamine-2 receptor antagonists and proton pump inhibitors, and cytoprotective drugs such as prostaglandin analogues and mucosal protectors.

Antacids contain aluminium/magnesium hydroxide and/or magnesium/calcium carbonates. They are indicated for gastritis, ulcers and reflux oesophagitis since they neutralise acid in the gastric lumen. The effect of antacids is rapid in onset (30 minutes) but short in duration (2–3 hours). Possible side effects are acid rebound if not given frequently, alteration of drug absorption and cation-dependent side effects, such as constipation for aluminium and calcium, hypophosphataemia for aluminium, hypercalcaemia for calcium and diarrhoea for magnesium. In animals with renal failure, cardiac diseases or pregnancy, their use can result in severe electrolyte imbalances with dangerous consequences. In veterinary medicine, antacids are FDA approved for large animals, but their effect has never been studied in clinical trials with dogs or cats. Changes in food taste and the frequency of necessary dosing (six times daily) cause compliance problems for animals and owners. Therefore, they have rather low value in treating gastric disorders in dogs and cats.

H2 receptor antagonists (e.g., cimetidine, ranitidine, famotidine) are competitive antagonists of histamine at the H2 receptor of the parietal cell. In the stomach, they cause a decrease in meal-stimulated acid secretion and an increase of luminal bicarbonate, mucus secretion and mucosal blood flow. Reported side effects are bradycardia, hypotension and vomiting when given as rapid intravenous injection. Therefore, oral, subcutaneous and slow intravenous (CRI) administration are preferred. Their value in influencing gastric disorders in dogs differs between the members of the class.

 Cimetidine has no effects on mechanically and aspirin-induced ulcers in dogs, does not influence ulcer development in dogs receiving high-dose methylprednisolone and undergoing spinal surgery, and has no effect on barrier or metabolic functions in an ex vivo canine gastric chamber model. Additionally, cimetidine interferes with drug metabolism due to negative effects on liver perfusion and the inhibition of P450 enzymes. This leads to a decreased metabolism mainly of beta-blockers, calcium-channel blockers, lidocaine, barbiturates, benzodiazepines, xanthines, warfarin, metronidazole and ciclosporin. Cimetidine is the licensed H2 receptor antagonist in the UK.

 Ranitidine is 5–12 times more potent and has fewer negative effects on P450 enzymes than cimetidine. It also possesses prokinetic effects on the stomach. At a dose of 5 mg/kg, it increases the gastric pH of dogs to > 7 within 1 hour after administration. However, at a dose of 2 mg/kg (i.v. q12h), the effect of ranitidine on gastric pH is not different from saline. Therefore, current dose recommendations (0.5–2 mg/kg q8–12h) seem to be too low to be of any effect. Currently, clinical studies on the effect of ranitidine on gastric disorders in dogs and cats are lacking.

 Famotidine (0.5 mg/kg i.v. q12h) increased the gastric pH in dogs significantly when compared to saline and prevented exercise-induced gastritis in racing Alaskan sled dogs. It is currently the only H2-receptor blocker with some proven evidence for a gastroprotective effect in dogs, although it is not licensed for use in animals in the UK.

Proton pump inhibitors (e.g., ome-, esome-, lanso-, pantoprazole) are the most potent gastric acid inhibitors causing long-lasting and pronounced reduction of acid secretion. They are 20 times more potent than cimetidine and they are mainly indicated to treat erosive oesophagitis, and gastric ulcers due to non-steroidal anti-inflammatory drugs (NSAIDs), mast cell tumours and gastrinoma. Pantoprazole (1 mg/kg i.v. q24h) and omeprazole suspension (1 mg/kg orally q24h) significantly suppressed gastric acid secretion in healthy dogs to a level of potential therapeutic efficacy for the healing of duodenal ulcers when assessed by criteria for human patients. Omeprazole has been of higher efficacy than famotidine in reducing exercise-induced gastric lesions in racing Alaskan sled dogs but has no effect in preventing or healing gastric mucosal lesions in dogs with intervertebral disc disease. None of these drugs is licensed for use in animals in the UK.

Prostaglandin analogues (e.g., misoprostol: 1–5 µg/ kg orally q8h) increase gastric mucus and bicarbonate production, and inhibit the proton pump to some extent. Side effects include stimulation of intestinal motility and secretion as well as uterine contractions (abortion is possible). Misprostol was shown to be effective in preventing aspirin-induced gastroduodenal ulceration in two of three studies performed in dogs. No effect was seen in dogs undergoing spinal surgery and receiving high doses of methylprednisolone.

The mucosal protector sucralfate (0.5–1 g/dog orally q8h) acts by forming an adhering sucrose octasulfate complex with high affinity to damaged mucosa. In rats, it accumulates on induced gastric ulcers for 8 hours and on duodenal ulcers for about 4 hours. Positive effects in dogs with gastric ulcers have been repeatedly reported but clinical studies are lacking. Sucralfate should be given separately to other drugs since it has negative influence on drug absorption. Rare side effects are constipation and hypophosphataemia.

References

1.  Bersenas AM, Mathews KA, et al. Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs. American Journal of Veterinary Research 2005;66:425–431.

2.  Conder GA, Sedlacek HS, et al. Efficacy and safety of maropitant, a selective neurokinin 1 receptor antagonist, in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs. Journal of Veterinary Pharmacology and Therapy 2008;31:528–532.

3.  de la Puente-Redondo VA, Siedek EM, et al. The anti-emetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe. Journal of Small Animal Practice 2007;48:93–98.

4.  Elwood C, Devauchelle P, et al. Emesis in dogs: a review. Journal of Small Animal Practice 2010;51:4–22.

5.  Sedlacek HS, Ramsey DS, et al. Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally or peripherally acting emetogens in dogs. Journal of Veterinary Pharmacology and Therapy 2008;31:533–537.

  

CONTACT US

777 W. Covell Blvd., Davis, CA 95616

mailto:vingram@vin.com

PHONE

  • Toll Free: 800-700-4636
  • From UK: 01-45-222-6154
  • From anywhere: (1)-530-756-4881
  • From Australia: 02-6145-2357
SAID=27