Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used routinely in human and veterinary medicine as anti-inflammatory, analgesic, and antipyretic agents.1 It is very likely that pet owners will have over-the-counter NSAIDs in their homes for their own use and potentially NSAIDs prescribed for their animals too. Consequently, NSAID intoxication is one of the most common encountered in small animals. This lecture will briefly review pharmacology of NSAIDs, organ system dysfunction associated with toxicity, decontamination strategies for asymptomatic patients, and a review of traditional and novel therapies for NSAID intoxication.
NSAID Pharmacology
NSAIDs are direct cyclo-oxygenase (COX) inhibitors.1,2 Arachidonic acid becomes liberated from plasma membranes following trauma or during inflammation. Arachidonic acid may be converted to a diverse group of chemicals, called eicosanoids, under the action of COX. The eicosanoids represent several chemical groups including prostaglandins, thromboxanes, and leukotrienes. Different isoforms of COX exist and traditionally a distinction has been made between the functions of the COX-1 and COX-2 enzymes. It has been suggested that COX-1 enzymes are primarily ‘housekeeping’ enzymes, leading to eicosanoid production necessary for maintenance of homeostasis, while COX-2 are inducible enzymes upregulated during periods of inflammation. This distinction is likely an oversimplification but has led to the development of drugs with increased selectivity for COX-2 over COX-1 with the hope of a more favourable safety profile. Aspirin is the prototypical NSAID and is a non-selective, irreversible COX inhibitor. Most modern NSAIDs used in people and animals are reversible and have COX-2 selectivity. Paracetamol (acetaminophen) is sometimes erroneously thought to be an NSAID but is not a COX inhibitor and will not be discussed further in this lecture. Most NSAIDs are absorbed rapidly from the GI tract with peak plasma concentrations typically occurring 2–4 hours after ingestion. They are highly protein bound and, therefore, have a small volume of distribution. Most NSAIDs undergo extensive enterophepatic recirculation and undergo glucuronidation in the liver before elimination via the urine. The elimination half-lives of NSAIDs are quite variable. Naproxen has the longest half-life in dogs (e.g., 74 hours).1
Organ Dysfunctions in NSAID Intoxication
Most NSAID intoxications occur either when owners intentionally provide NSAIDs to their pets or when animals voluntarily ingest them. The latter may occur especially when pets have access to palatable versions of NSAIDs. The major adverse effects associated with NSAID intoxication are gastrointestinal, renal, haematological, hepatic and central nervous system dysfunctions.
Gastrointestinal system: Prostaglandins are needed for gastric mucosal health by promoting mucus production in the stomach and maintaining normal perfusion in the intestines. COX inhibition leads to fewer prostaglandins, impaired mucosal protection and risks gastrointestinal ulceration, especially in the stomach and duodenum. NSAIDs also impair the healing of pre-existing ulcers by limiting perfusion to the region. The consequences of NSAID ingestion are dose dependent and common symptoms include inappetence, vomiting, diarrhoea, melaena, and haematemesis (‘coffee grounds’ vomitus). If significant GI losses occur, the patient may become dehydrated and even hypovolaemic, especially if significant haemorrhage occurs. Acute laboratory changes may include regenerative anaemia with hypoproteinaemia and elevated BUN relative to creatinine. It is important to realize that the haematological changes in cases of chronic GI bleeding, for example associated with long-term NSAID usage, are different and typically a non-regenerative microcytic hypochromic anaemia develops.
Kidneys: Acute kidney injury is concerning particularly when higher doses are ingested or in patients with pre-existing volume depletion. When there is renal hypoperfusion, glomerular filtration rate is reduced and prostaglandins are released from the juxtaglomerular apparatus. These prostaglandins induce vasodilation of the afferent arteriole thereby maintaining renal blood flow and glomerular filtration function despite volume depletion. COX inhibition limits this renoprotective mechanism and glomerular filtration may drop to dangerously low levels. Pathological lesions associated with NSAID nephrotoxicity include papillary necrosis and interstitial nephritis.
Haematological: COX inhibition by NSAIDs will impair thromboxane production, which is an activator of platelets, and, therefore, NSAID intoxication risks development of platelet dysfunction. Therapeutically aspirin is used for this purpose in patients at risk of or with confirmed thromboembolic disease. Aspirin causes irreversible COX inhibition for the life of the platelet (about one week), whereas newer NSAIDs may induce less pronounced platelet inhibition.
Hepatic: Liver injury secondary to NSAID intoxication appears to be relatively uncommon. Some idiosyncratic reactions have been reported in dogs following NSAID ingestion at appropriate doses (e.g., Labradors and carprofen). The potential for hepatotoxicity may be more pronounced if pre-existing liver disease exists.
Central nervous system: Various symptoms attributable to CNS dysfunction (e.g., depression, seizures, ataxia) may be seen in animals following NSAID ingestion. In people, aseptic meningitis has also been reported.
Management of NSAID Toxicity
Prompt treatment should always be instituted in animals exposed to NSAIDs. Decontamination strategies are appropriate for animals that have recently ingested NSAIDs and have not yet exhibited overt clinical signs. Decontamination strategies usually include administration of an emetic substance (e.g., apomorphine to dogs, dexmedetomidine or xylazine to cats) provided no contra-indication exists (e.g., neurological impairment). After induction of emesis, activated charcoal is usually administered. Conventionally, multiple doses have been given especially in light of the enterohepatic recirculation but single doses may be as effective as multiple.3 After decontamination, forced diuresis with intravenous crystalloids has traditionally been recommended often for prolonged periods of time (e.g., three half-lives of the drug according to some sources). Gastroprotectant medications are also often prescribed, which may include a combination of H2 receptor antagonists (e.g., famotidine); proton pump inhibitors (e.g., omeprazole); synthetic prostaglandin analogs (e.g., misoprostol), and medications to provide a physical barrier to acid injury (e.g., sucralfate). In cases of clinically relevant anaemia secondary to GI bleeding, packed red blood cell transfusions may be indicated in patients. In some instances, gastric ulcerations may perforate and lead to septic peritonitis, for which exploratory surgery and antimicrobials will be initiated.
Recently there has been growing interest in alternative means of managing NSAID toxicity. One management strategy involves the administration of intravenous lipid.4,5 Intralipid therapy has been used in small animals for a variety of lipophilic toxins.6 The most widely accepted explanation for lipid therapy, is the creation of a lipid sink within the intravascular space into which lipophilic compounds can become sequestered. Adverse effects of lipid therapy appear rare but may include pancreatitis and volume overload in susceptible patients. While intralipid therapy can be performed in most practices without the need for specialist equipment, the emerging gold standard means of managing NSAID toxicity involves extracorporeal therapies. Traditional haemodialysis is unlikely to be effective as a sole treatment since NSAIDs are highly protein bound and do not readily diffuse across traditional dialyzers well.7 A more effective method involves the addition of a charcoal cartridge to a haemodialysis circuit.7 These filters enable removal of highly protein and lipid soluble drugs and combined haemoperfusion and haemodialysis has been described in a dog that ingested ibuprofen. An alternative blood purification technique involves therapeutic plasma exchange (TPE) or plasmapheresis. This process involves the separation of the plasma and cellular components of blood, with substances confined to the plasma being effectively removed using an extracorporeal circuit, before replacing the patient’s blood with donated plasma or a combination of donated plasma and synthetic colloids. This technique has been used extensively in human medicine for decades and is best suited for toxins with high protein binding and small volumes of distribution. There are reports of several NSAIDs intoxications being successfully treated with TPE in dogs and it appears to be a reliable option even when high doses have been ingested.8-11 Adverse effects have been reported frequently with the technique although they appear not to impact outcome for patients.
References
1. McLean MK, Khan SA. Toxicology of frequently encountered nonsteroidal anti-inflammatory drugs in dogs and cats: an update. Vet Clin Small Anim Pract. 2018;48:969–984.
2. Borchers A. Non-steroidal anti-inflammatory drug intoxications. In: Drobatz KJ, Hopper K, Rozanski EA, Silverstein D, eds. Textbook of Small Animal Emergency Medicine. Hoboken, NJ: Wiley and Sons; 2018:856–861.
3. Koenigshof AM, Beal MW, et al. Effect of sorbitol, single, and multidose activated charcoal administration on carprofen absorption following experimental overdose in dogs. J Vet Emerg Crit Care. 2015;25(5):606–610.
4. Bolfer L, McMichael M, Ngwenyama TR, O’Brien MA. Treatment of ibuprofen toxicosis in a dog with IV lipid emulsion. J Am Anim Hosp Assoc. 2014;50(2):136–140.
5. Herring JM, Mcmichael MA, Corsi R, Wurlod V. Intravenous lipid emulsion therapy in three cases of canine naproxen overdose. J Vet Emerg Crit Care. 2015;25(5):672–678.
6. Robben JH, Dijkman MA. Lipid therapy for intoxications. Vet Clin North Am Small Anim Pract. 2017;47(2):435–450.
7. Tauk BS, Foster JD. Treatment of ibuprofen toxicity with serial charcoal hemoperfusion and hemodialysis in a dog. J Vet Emerg Crit Care. 2016;26(6):787–792.
8. Rosenthal MG, Labato MA. Use of therapeutic plasma exchange to treat nonsteroidal anti-inflammatory drug overdose in dogs. J Vet Intern Med. 2019;33(2)596–602.
9. Walton S, Ryan KA, Davis JL, Acierno M. Treatment of ibuprofen intoxication in a dog via therapeutic plasma exchange. J Vet Emerg Crit Care. 2017;27(4):451–457.
10. Walton S, Ryan KA, Davis JL, Acierno M. Treatment of meloxicam overdose in a dog via therapeutic plasma exchange. J Vet Emerg Crit Care. 2017;27(4):444–450.
11. Kjaergaard AB, Davis JL, Acierno MJ. Treatment of carprofen overdose with therapeutic plasma exchange in a dog. J Vet Emerg Crit Care. 2018;28(4):356–360.