Equis ISSN 2398-2977

Toxicity: non-steroidal anti-inflammatory (NSAID)

Synonym(s): Non-steroidal anti-inflammatory drug toxicity

Contributor(s): Christopher Brown, Rachael Conwell, Wilson Rumbeiha, Vetstream Ltd

Introduction

  • The toxicity of phenylbutazone, flunixin meglumine, suxibuzone and ketoprofen has been studied experimentally. Phenylbutazone has been shown to be the most likely NSAID to result in toxicity, although all NSAIDs have potential toxic side effects, particularly where concurrent disease is present. Toxicity is more likely when different NSAIDs are administered in combination, or alongside other nephrotoxic drugs, such as gentamicin, in dehydrated horses.
  • Signs: as with most species, the most common manifestation of NSAID toxicity is gastrointestinal ulceration, particularly the glandular region of the stomach, proximal duodenum and the right dorsal colon. This results in colic, diarrhea, dehydration and weight loss. Other effects include blood dyscrasias and renal papillary necrosis.
  • Diagnosis: can be challenging due to non-specific clinical findings. A history of recent NSAID administration is suspicious, but toxicity is not always associated with prolonged use of overdose and doses may be within the therapeutic range and for short duration.
  • Treatment: cessation of NSAID administration and supportive therapy, including dietary modification.
  • Prognosis: early recognition and treatment is vital for a successful outcome. Delayed diagnosis and severe pathology, such as stricture or rupture of the right dorsal colon, have poor prognosis.

Pathogenesis

Etiology

  • Non-steroidal anti-inflammatory drugs (NSAIDs) Therapeutics: anti-inflammatory drugs are used for reducing inflammation, providing analgesia and for anti-endotoxic effects. They are inhibitors of the enzyme cyclo-oxygenase (COX), thus preventing formation of inflammatory mediators.
  • NSAID toxicity can occur due to direct toxic effect or as a result of COX inhibition. 
  • There are two groups: enolic acids, eg phenylbutazone Phenylbutazone, and carboxylic acids, eg flunixin Flunixin meglumine.

Predisposing factors

General

  • There is increased risk of nephrotoxicity if NSAIDs are administered to horses with dehydration, hypovolemia, pre-existing renal disease or who are already receiving other nephrotoxic drugs.
  • Gastrointestinal toxicity is more likely if there is concurrent dehydration, endotoxemia or underlying gastrointestinal disease.

Specific

  • High doses have increased risk of toxicity; however, horses can also show evidence of toxicity when administered NSAIDs at recommended doses.
  • Prolonged duration of treatment is associated with increased risk, but horses can develop NSAID toxicity after short duration of therapy.

Pathophysiology

  • Act by inhibiting cyclo-oxygenase, thus preventing formation of inflammatory mediators.
  • Inhibition of vasodilatory prostaglandin synthesis may → toxic effects.
  • Direct toxic effects of NSAIDs or their metabolites, which accumulate in the renal medulla and cause local cellular necrosis; similar direct toxic effect on gastric mucosa and possibly in right dorsal colon.
  • Toxicity is also possible due to NSAID inhibition of cyclo-oxygenase.
  • There are two main recognized forms of the COX enzyme, COX-1 and COX-2.
  • COX-1 is constitutively expressed in most tissues and is responsible for prostaglandin production during normal physiological processes. In the gastrointestinal tract, prostaglandins are necessary for maintenance of mucosal integrity and blood flow and for restoration of mucosal barrier function after injury. In the kidney, prostaglandins have a vasodilatory effect to maintain blood flow, particularly to the renal papillae.
  • COX-2 is expressed at low levels in normal tissue and is upregulated in response to injury.
  • NSAIDs such as phenylbutazone Phenylbutazone and flunixin meglumine Flunixin meglumine are non-selective COX inhibitors, inhibiting both COX-1 and COX-2, with resultant potential toxic side-effects. Phenylbutazone in particular is most associated with gastrointestinal toxicity. More selective COX-2 inhibitors, such as meloxicam Meloxicam and firocoxib Firocoxib, are less likely to have toxic effects.
  • Inhibition of vasodilatory functions of prostaglandins → decreased blood flow to intestinal mucosa and kidney → ischemia and hypoxia → gastrointestinal ulceration; renal papillary necrosis.
  • This can result in clinical signs such as polyuric renal failure or diarrhea due to protein-losing enteropathy Protein losing conditions.
  • Hepatoxicity and hematologic abnormalities have also been reported.

Timecourse

  • Usually chronic but can occur acutely.

Epidemiology

  • Usually due to therapeutic administration.
  • More likely in young performance horses receiving NSAIDs for orthopedic injury.

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • DArcy-Moskwa E et al (2012) Effects of meloxicam and phenylbutazone on equine gastric mucosal permeability. J Vet Intern Med 26 (6), 1494-1499 PubMed.
  • Marshall J F & Blikslager A T (2011) The effect of nonsteroidal anti-inflammatory drugs on the equine intestine. Equine Vet J 43 (39), 140-144 PubMed.
  • Lane J K et al (2010) Right dorsal colon resection and bypass for treatment of right dorsal colitis in a horse. Vet Surg 39 (7), 879-883 PubMed.
  • McConnico R S et al (2008) Pathophysiologic effects of phenylbutazone on the right dorsal colon in horses. Am J Vet Res 69 (11), 1496-1505 PubMed.
  • Jones S L, Davis J & Rowlington K (2003) Ultrasonographic findings in horses with right dorsal colitis: five cases (2000-2001). JAVMA 222 (9), 1248-1251 PubMed.
  • Cohen N D (2002) Right dorsal colitis. Equine Vet Educ 14 (4), 212-219 VetMedResource.
  • Moore V S & Bertone A L (2002) Nonsteroidal anti-inflammatory drugs. Vet Clin N Am Eq Pract 18 (1), 21-37 PubMed.
  • Macallister C G, Morgan S J, Borne A T & Pollet R A (1993) Comparison of adverse effects of phenylbutazone, flunixin meglumine and ketoprofen in horses. JAVMA 202 (1), 71-77 PubMed.

Other sources of information

  • Davis E G (2005) Right Dorsal Colitis and Dietary Management. In: Proc of the North Am Vet Conference Large Animal. Vol 19, Orlando, USA. pp 147-149.
  • Mitten L A & Hinchcliff K W (1997) Non-Steroidal Anti-Inflammatory Drugs. In: Current Therapy in Equine Medicine IV. Ed: N W Robinson. W B Saunders, UK. pp 724-727.


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