Anti-inflammatories for dogs. Uses and side effects

Introduction

The family of anti-inflammatories encompasses a wide range of drugs that are primarily intended to reduce inflammation, pain and fever. Glucocorticoids and nonsteroidal anti-inflammatory agents (NSAIDs) are used frequently in small animal medicine. These two groups of drugs are powerful anti-inflammatories and are used to treat a wide variety of diseases. Their main anti-inflammatory actions include the suppression of proinflammatory substances and other inflammatory mediators, which influences the functions of the metabolic and immune systems. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) usually have a more potent action, but they also have more negative short-term effects for animals, particularly dogs. Glucocorticoids, however, are less specific and can have serious medium- and long-term effects. The pharmacology, clinical indications and side effects of each class of drug are discussed below.

Main side effects of the sustained use of corticosteroids

Corticosteroids are lipophilic drugs that penetrate cells through passive diffusion. When they bind to their cytoplasmic receptor, they are dimerised and pass into the nucleus where they act on the DNA and influence gene regulation and other transcription factors. Glucocorticoids exert an anti-inflammatory action by disabling the genes that code for cytokines, chemokines and other inflammatory mediators, including adhesion molecules, inflammatory peptides and mediator receptors.

Glucocorticoids reduce the movement and activity of white blood cells and fibroblasts and inhibit the expression of cyclooxygenase (COX)-2, cytokines, cell adhesion factors and histamine release. They may have immunosuppressant or anti-inflammatory activity depending on the dose. However, they also produce unwanted side effects, especially during long-term treatment, including:

• Immunosuppression. Corticosteroids inhibit COX-2 and the production of proinflammatory cytokines and adhesion molecules. They also reduce macrophage activity, thus supressing the synthesis of antibodies and number of T cells. This means they have a significant immunosuppressive effect which, although it may be beneficial in the treatment of immune-mediated diseases, can also be harmful as it predisposes the animal to different types of opportunistic infection. 
   
• Gastrointestinal ulcers. Some of the most common side effects of corticosteroids, especially when used at high doses, are vomiting, diarrhoea and gastrointestinal ulcers. Some of these effects are due to their inhibitory action on prostaglandin synthesis. These prostaglandins are involved in the mechanisms that protect the gastric mucosa and proximal portion of the duodenum, so inhibiting their production can cause gastroduodenal ulcers or perforation. There is no evidence that the addition of gastroprotectants stops them from developing and therefore their combined use is not advisable on a routine basis. Similarly, glucocorticoids should not be coadministered with NSAIDs due to the increased risk of gastrointestinal ulceration. 
   
• Diabetes. Corticosteroids have an antagonistic effect on insulin, accelerate gluconeogenesis and inhibit the peripheral use of glucose, all of which increases glycogen deposition in the liver. This mechanism can induce hyperglycaemia, which can cause some animals (above all cats) to develop diabetes, especially those already in a prediabetic state. Another effect on the endocrine systemis iatrogenic hyperadrenocorticism, where excess cortisol may cause symptoms associated with Cushing’s syndrome (polyuria, polydipsia, alopecia, pendulous abdomen, etc.). There is also a decline in thyroid hormone production.
   
• Cardiovascular problems. Glucocorticoids can affect heart muscle function and cause fluid retention. As such, they should be used with caution in patients with heart disease, since congestive heart failure is a potential risk, especially in cats.
   
• Delayed wound healing/sarcopenia/decreased bone resorption. Corticosteroids block protein anabolism and the proliferation of fibroblasts and collagen, which can cause muscle atrophy and weakness, a loss of bone matrix and a decline in longitudinal bone growth. These mechanisms explain both the delayed growth of young animals and problems with wound healing. Consequently, they should not be used following surgery or in patients with an open wound.
   
• Renal effects. Glucocorticoids increase glomerular filtration rate. They also inhibit antidiuretic hormone, leading to polyuria and polydipsia. Increased proteinuria. Water, sodium and chloride retention. Increased excretion of potassium and calcium. 
   
• Behavioural changes. Animals treated with corticosteroids were significantly less playful, more nervous and restless, more fearful, less confident and tended to avoid unfamiliar people or new situations. And they may also have polyphagia.
   
• Effects on blood count, blood chemistry and coagulation. Increased number of mature circulating neutrophils, fewer lymphocytes and eosinophils. Erythrocytosis, thrombocytosis and hypercoagulability. These patients are more likely to develop thromboembolisms. Elevated liver enzymes, especially alkaline phosphatases in dogs.

Main side effects of using nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of drugs with analgesic and anti-inflammatory properties. They are often used as anti-inflammatories and analgesics in veterinary medicine. 

NSAIDs are selective inhibitors of COX-1, COX-2, COX-1 and COX-2 or COX-3, resulting in reduced prostaglandin synthesis. The levels of these molecules can increase in inflammatory states, but they also have a constitutive function and are involved in various homeostatic functions.

The side effects of NSAIDs are related to the inhibition of the constitutive functions of COX-1, COX-2 and COX-3, while the selectivity of their inhibition depends on which NSAID is used. Some inhibit COX-1 and COX-2 (aspirin, phenylbutazone, ketoprofen, flunixin meglumine); others preferably inhibit COX-2 and to a lesser extent COX-1 (meloxicam, carprofen, etodolac, tolfenamic acid). Others selectively inhibit COX-2 (deracoxib, firocoxib, robenacoxib). Finally, some NSAIDs produce more COX-3 inhibition. In overweight or obese patients, it is important to note that dosage calculations for NSAIDs should be based on ideal body weight rather than actual weight.

• Gastrointestinal ulcers. Some of the most common side effects of NSAIDs, particularly at high doses, are vomiting, diarrhoea and gastrointestinal ulcers/perforation. Their mechanism of action inhibits some of the mechanisms that protect the gastric and duodenal mucosa. There is no evidence that the addition of gastroprotectants stops them from developing and therefore their combined use is not advisable on a routine basis. Similarly, NSAIDs should not be coadministered with glucocorticoids as it introduces an increased risk of gastrointestinal ulceration. 
   

NSAIDs should not be administered to patients with acute renal injury or uraemia, liver failure, dehydration, hypotension or conditions associated with low “effective circulating volume”. In hypovolaemic situations, secondary renal injury can occur following NSAID administration due to the inhibition of the synthesis of prostaglandins which physiologically protect renal function. Consequently, blood tests are always recommended before prescribing NSAIDs to determine baseline values, and they should be repeated periodically. Obviously, these drugs should be used with extreme caution in animals with an underlying liver or kidney disease. Other side effects linked to the use of NSAIDs in veterinary medicine include reduced capacity for platelet aggregation, negative effects on the reproductive tract and foetus, such as abortion, ovulation disorders and egg implantation defects in the uterus, vascular abnormalities in the foetus, and so on.

References

• Masters, AK et. al. (2018) Effects of short-term anti-inflammatory glucocorticoid treatment on clinicopathologic, echocardiographic, and hemodynamic variables in systemically healthy dogs. Am J Vet Res; 79(4): 411-423.

• Notari, L et. al. (2015) Behavioural changes in dogs treated with corticosteroids. Physiol Behav; 151: 609-616.

• Monteiro-Steagall BP, Steagall PV, Lascelles BD. Systematic review of nonsteroidal anti-inflammatory drug-induced adverse effects in dogs. J Vet Intern Med. 2013 Sep-Oct;27(5):1011-9. doi: 10.1111/jvim.12127. Epub 2013 Jun 19. Erratum in: J Vet Intern Med. 2014 Mar-Apr;28(2):745. PMID: 23782347.

• Blois. S, Mathews. KA. CHAPTER 16. Anti-Inflammatory Therapy. Textbook of Veterinary Internal Medicine. Ettinger.S, et al. 8th Ed. 2016. Saunders. USA.