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Basic gastrointestinal therapeutics

Author : REBECCA LITTLER

Categories : Vets

Date : January 13, 2014

REBECCA LITTLER gives details of the various options available for treating gastrointestinal symptoms in cats and dogs

THERAPEUTIC intervention may be required for acute or chronic disease, or as part of a preventive health care protocol – for example, anthelmintics.

Many gastrointestinal (GI) cases presented to the general practitioner are acute and self-limiting, and only symptomatic or supportive therapy is required. Certain conditions have specific treatments and symptomatic therapy should be reassessed after 48 to 72 hours if the patient is not improving so a definitive diagnosis can be explored.

Chronic GI diseases, such as inflammatory bowel disease (IBD), have specific therapeutic modalities and combinations of drug classes may be required. It is important to understand the mode of actions of these drugs so any potential drug interactions or adverse reactions can be quickly identified. For drug doses, the clinician is referred to the BSAVA Small Animal Formulary, 7th edition.

Anthelmintics

A variety of wormers are available on the market and most practices will have a standard worming policy for dogs and cats. These products are used preventively and therapeutically, and often to treat protozoal infections as well as worms. The most important worms in UK pets are shown in Table 1, with some of the common wormer types effective against them.

1 / 10 Always check the worming programme used is effective against all types of worms likely to be encountered – for example, it might be tempting to inject a difficult-to-pill cat with praziquantel, but this will not kill any roundworms.

Fenbendazole is especially useful in the treatment of GI protozoal infections such as Giardia; however, a higher, more prolonged dose is required than for standard worming and this should be checked. Tritrichomonas, the large intestinal parasite of cats, requires treatment with ronidazole.

Anti-emetics

Anti-emetics are useful in acute vomiting – especially where the patient is at risk of dehydration or to allow early introduction of enteral nutrition, for example, in pancreatitis. They may be used in chronic cases where vomiting is present – for example, during cancer chemotherapy or severe IBD.

The vomiting mechanism is protective, however, and the clinician should always be alert to the possibility of masking a total or partial bowel obstruction.

Maropitant

Work has identified substance P and the neurokinin-1 (NK1) receptor are integral parts of the vomiting reflex. Therefore, antagonism of the NK1 receptor by maropitant offers veterinarians an alternative to traditional anti-emetics.

This drug is also useful in pancreatitis as antagonism of the NK1 receptor is important in relief of pain in this situation. Maropitant is formulated in both injectable and oral forms. At the moment, the drug does not have a licence in cats, but has been used effectively.

Metoclopramide

Metoclopramide is an antiemetic, as well as an upper GI prokinetic, and, therefore, may be of use where ileus contributes to ongoing vomiting. Peripherally, it sensitises tissue to acetylcholine, which increases lower oesophageal sphincter pressure and the tone/amplitude of the gastric contraction.

Centrally, the drug blocks dopamine and 5-HT3 serotonergic receptors in the chemoreceptor trigger zone (CRTZ). The efficacy of metoclopramide is perceived to be increased by administering the drug as a constant rate intravenous infusion. Do not use metoclopramide where GI obstruction or perforation is considered likely.

Metoclopramide is light-sensitive and should be stored in light-resistant containers. This should also be considered when using the drug as a constant rate infusion and wrapping or covering an infusion is indicated. Forms available are an injectable solution, oral tablets and syrup. Cats can

2 / 10 infrequently show disorientated and frenzied behaviour. Hyper excitability is also infrequently reported in the dog.

Anti-emetics used off licence in dogs and cats

Phenothiazines

Phenothiazines work by antagonising dopamine (D2) receptors, histamine H1 and H2 receptors and muscarinic cholinergic receptors. At high dose, phenothiazines also antagonise the alpha-1 and alpha-2 adrenergic receptors at the vomiting centre. Prochlorperazine is less sedative than other phenothiazines. The obvious drawback of this drug group is the arteriolar dilation resulting in hypotension. Therefore, these drugs cannot be considered until a patient is stable and fluid deficits have been addressed.

Ondansetron

Ondansetron is a highly selective serotonin (5-HT3) antagonist and is a potent anti-emetic. Its precise mode of action in the control of nausea and vomiting is not known. In humans, it is used to control nausea and vomiting induced by chemotherapy. In this situation, it is thought the drug antagonises 5-HT3 receptors in the peripheral and central nervous system (CNS).

The main limiting factor of this drug is the potential high costs involved and it is, therefore, reserved for cases of refractory vomiting. Injectable, tablet or syrup forms are available. Side effects in man include constipation and headaches and rarely hypersensitivity reactions have occurred. The author is not aware of any well-documented side effects in dogs and cats.

Reducing acid secretion and providing mucosal protection

Drugs that reduce acid secretion and provide mucosal protection are indicated in the treatment of gastric or duodenal ulcers, non-specific gastritis and in hypersecretory conditions such as gastrinoma or systemic mastocytosis. If oesophagitis is present, antacids and mucosal protectants are also indicated (Figure 1).

Drugs used to decrease acid secretion may include:

• H2 blockers. These drugs are reversible competitive antagonists of the H2 receptor. This blocks histamine-induced gastric acid and pepsin secretion. These drugs have been used widely, but are not licensed for veterinary use.

• Cimetidine. Has the longest history of veterinary use. It can be given both intravenously and orally; however, its pharmacokinetics require it to be given four times daily. It is metabolised by the liver and affects hepatic cytochrome P450 activity, meaning care with dosage of drugs such as

3 / 10 ciclosporin, ketoconazole, diltiazem and metronidazole are required to avoid toxicity. It would be wise to use an alternative H2 blocker where hepatic impairment is present.

• Ranitidine. Has a longer duration of action than cimetidine and only has to be given twice daily. It does not have the hepatic side effects of cimetidine and has a mild prokinetic effect, which can be of benefit where ileus or poor gastrointestinal motility is present.

• Famotidine. Is up to 20 to 50 times more potent than cimetidine. Its duration of action means oncedaily dosing only is required. This can be useful in cats or difficult-to-pill animals.

Proton pump inhibitors

Omeprazole

Proton pump inhibitors irreversibly bind to the proton pump, which forms the final step in acid secretion. There are no veterinary licensed products.

Omeprazole is approximately 20 to 30 times more potent than H2 blockers; however, it takes 48 to 72 hours to reach therapeutic levels in the blood stream and, therefore, where rapid decrease in acid secretion is required, overlapping with H2 blockers should be considered.

Omeprazole is available in capsules, which, if split, should be reconstituted into other capsules as the drug is unstable in an acid environment. It is the treatment of choice in severe ulceration hypersecretion syndromes, such as Zollinger-Ellison syndrome or mastocytosis, and is available in oral and injectable forms.

As omeprazole is a very potent antacid, it can cause reflex hypergastrinaemia and potentially hypertrophic gastritis.

Mucosal protectants

Drugs used as mucosal protectants include:

Prostaglandins

Prostaglandin E2 (PGE2) analogue misoprostol protects against NSAID damage without blocking acid secretion. This drug may cause diarrhoea and must not be given to pregnant animals. It is not effective at healing pre-existing ulcers, but may be of use in dogs that need to take longterm NSAIDs. Sucralphate Sucralphate (polyaluminium sucrose) binds to areas denuded of mucosal epithelium, forming a barrier against the penetration of gastric acid. Sucralphate also may stimulate endogenous prostaglandins, increase epidermal growth factor and mucosal blood flow and inactivate pepsin. It is available as both a liquid and a tablet form, neither of which have a

4 / 10 veterinary licence.

It is probably best to separate sucralphate administration from that of other drugs as it may inhibit their absorption. Evidence for and against this is unclear; however, antibiotics must be given two hours before sucralphate.

Antibiotics

On the whole, cases of mild or acute gastroenteritis do not need treatment with antibiotics. Antibiotics should be confined to those cases that are systemically unwell. The following situations would indicate the prescription of antibiotics:

• specific infections – for example, Salmonella or Campylobacter;

• haemorrhagic diarrhoea due to the risk of sepsis with mucosal ulceration;

• antibiotic responsive diarrhoea (ARD) or small intestinal bacterial overgrowth (SIBO);

• severe immunosuppression; and

• aspiration pneumonia caused by regurgitation in oesophageal disease.

Macrolides – erythromycin

Erythromycin is the drug of choice for Campylobacter. It should be administered on an empty stomach and may cause vomiting. At a low dose, it acts as a motilin agonist and is prokinetic.

Metronidazole

Metronidazole is effective against many Gram-positive and most Gram-negative anaerobes. It can be used in conjunction with clavulanic acid-penicillin to provide broad-spectrum cover.

Metronidazole is employed in the treatment of antibiotic responsive diarrhoea and SIBO. It is of use in the treatment of Giardia. The possibility for CNS side effects should be noted.

Penicillins

Penicillins are most commonly employed as compounds with clavulanic acid when they are active against Gram-negatives and anaerobes in addition to their Gram-positive spectrum of activity. Although commonly employed as a first-line antibiotic in GI disease, early symptomatic or supportive therapy may be more beneficial.

5 / 10 Quinolones

Quinolones – bactericidal antibiotics, for example, enrofloxacin or marbofloxacin – are highly effective against Gram-negatives. They are effective in treatment of Salmonella and Campylobacter. Care is required and these drugs should be avoided in skeletal immature animals.

The treatment of boxer ulcerative colitis has been hugely improved by the use of these drugs. Quinolones are not a first-line treatment for GI disease and the clinician should ask himself or herself if they are really implicated before prescription.

Tetracyclines

Tetracyclines are bacteriostatic and are administered against many aerobes and atypical organisms. They should be given on an empty stomach. The disturbances they cause in the distribution of GI flora are of use in the management of antibiotic responsive diarrhoea.

Probiotics and prebiotics

Probiotics and prebiotics have the potential to modify the intestinal flora. A probiotic is a living organism that, upon ingestion, has benefits beyond nutrition. A probiotic may modulate the mucosal immune response by stimulating both innate phagocytic or specific secretory mechanisms.

Lactobacillus species are commonly used as probiotics. The organism should be carefully selected for the patient species, as it is unlikely those designed for human use would be beneficial to canine and feline patients.

Prebiotics are substrates for a limited number of beneficial bacterial species; most commonly non- digestible carbohydrates such as lactose or fructooligosaccharides are used.

Immunomodulation in canine and feline IBD

Corticosteroids

Prednisolone

Once lymphoma is ruled out, prednisolone is the treatment of choice in marked canine and IBD. The author always combines use of prednisolone with an exclusion diet. Prednisolone dose is initially high and then tapered at twoweekly intervals depending on clinical response.

Budesonide

6 / 10 Budesonide is a steroid preparation that shows extensive first pass in the liver and may therefore be useful in patients especially sensitive to steroids as systemic side effects are decreased. This drug is reportedly more ulcerogenic than prednisolone (Figure 2).

Therapy of refractory IBD cases

In human medicine, failure to respond to medical treatment with steroids is observed in 20 to 30 per cent of patients and a retrospective study of 80 dogs with IBD revealed 13 per cent of cases had intractable disease (Craven, 2004).

The following drugs may be used as an adjunct to steroid therapy, to reduce the steroid dose required or as alternative agents.

• Ciclosporin. Ciclosporin A has been shown to be effective in steroid refractory bouts of human IBD, and a study (Allenspach et al, 2006) has demonstrated its clinical effectiveness in dogs. Ciclosporin is metabolised via the cytochrome p450 system and care should be employed if given alongside drugs such as cimetidine. The bioavailability is variable among individuals.

• Chlorambucil, which may be beneficial in steroid refractory cases of IBD in cats.

• Azathioprine (not in cats).

This drug may take up to a week to reach therapeutic effectiveness. It is potentially hepatotoxic and myelosuppressive and monitoring of biochemistry and haematology with titration every other day dosing is essential.

Vitamin supplementation B12 and folate

Evidence from feline IBD suggests B12 deficiency may hamper gut healing and recovery in IBD. It is, therefore, advisable to measure B12 in cases of IBD in both dogs and cats and supplement parentally appropriately.

Folate may also be low in chronic GI disease and supplementation is recommended, especially while feeding a strict exclusion diet.

References and further reading

Allenspach K, Rüfenacht S, Sauter S et al (2006). Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroidrefractory inflammatory bowel disease, Journal of Veterinary Internal Medicine 20(2): 239-244. Craven M, Simpson J W, Ridyard A E et al (2004). Canine inflammatory bowel disease:

7 / 10 retrospective analysis of diagnosis and outcome in 80 cases (1995-2002), J Small Anim Pract 45(7): 336-342. Hall E, Simpson J and Williams D (2005). BSAVA Manual of Canine and Feline Gastroenterology (2nd edn), Blackwell Publishing Professional, Ames, Iowa, USA. Plumb D C (2011). Plumb’s Veterinary Drug Handbook (7th edn), Wiley-Blackwell. Ramsay I (2011). BSAVA Small Animal Formulary (7th edn), BSAVA, Gloucester.

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Figure 1. Control of gastric acid secretion by parietal cells. PPI – proton pump inhibitor. Musc. – muscarinic receptor.

Figure 2. Metabolism of budesonide.

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TABLE 1. Common worms in UK dogs and cats and anthelmintic susceptibility

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