Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) for DogsNSAIDs have the potential to relieve pain and inflammation without the myriad potential metabolic, hemodynamic, and immunosuppressive adverse effects how to boost testosterone with diet with corticosteroids. However, all NSAIDs have the potential for other adverse effects that should be considered in overall management of drugz inflammatory process. Unlike corticosteroids, which inhibit numerous pathways, NSAIDs act primarily to reduce the biosynthesis of prostaglandins by inhibiting cyclooxygenase COX. In nonsteroidal anti-inflammatory drugs for dogs, COX-2 is activated in damaged and inflamed tissues and catalyzes the formation of inducible prostaglandin, including PGE 2associated with intensifying the inflammatory response. COX-2 is also anti-indlammatory in thermoregulation and the pain response to injury.
Pros & Cons of Non-Steroidal Anti-Inflammatory Drugs for Dogs
NSAIDs have the potential to relieve pain and inflammation without the myriad potential metabolic, hemodynamic, and immunosuppressive adverse effects associated with corticosteroids. However, all NSAIDs have the potential for other adverse effects that should be considered in overall management of the inflammatory process. Unlike corticosteroids, which inhibit numerous pathways, NSAIDs act primarily to reduce the biosynthesis of prostaglandins by inhibiting cyclooxygenase COX.
In contrast, COX-2 is activated in damaged and inflamed tissues and catalyzes the formation of inducible prostaglandin, including PGE 2 , associated with intensifying the inflammatory response. COX-2 is also involved in thermoregulation and the pain response to injury. Although ratios of COX COX-2 inhibition by various NSAIDs in people and animals have been reported, caution is advised when interpreting such ratios, because they vary greatly depending on the selectivity assay used.
In general, drugs with ratios suggesting preferential activity against COX-2 may have fewer adverse effects due to COX-1 inhibition. COX-1—sparing drugs are associated with less GI ulceration and less platelet inhibition; however, it may be an oversimplification to assume that complete COX-2 inhibition is without potential risk.
Recent research has suggested that COX-2 can be induced constitutively in various organs, including the brain, spinal cord, ovary, and kidneys. In dogs, COX-2 mRNA is present in the loop of Henle and the maculae densa and may play an important role in the protective response to hypotension.
However, a study that failed to demonstrate COX-2 expression in canine kidneys raised questions regarding its role. COX-2 also appears to be important in the healing of GI ulcers in people, and certain COX-2—specific inhibitors delay ulcer healing experimentally.
Although COX-1 plays a primary role in regulating homeostasis, it may play a more significant role in inflammation than originally proposed.
Aspirin is unusual in that it irreversibly acetylates a serine residue of COX, resulting in a complete loss of COX activity. Unlike aspirin , most other NSAIDs including salicylic acid, an active metabolite of aspirin are reversible competitive COX inhibitors; their duration of inhibition is primarily determined by the elimination pharmacokinetics of the drug.
All NSAIDs, except for acetaminophen also named paracetamol , are antipyretic, analgesic, and anti-inflammatory. They are routinely used for the relief of pain and inflammation associated with osteoarthritis in dogs and horses and for colic, navicular disease, and laminitis in horses. As analgesics, they are generally less effective than opioids and are therefore generally indicated only against mild to moderate pain in people.
However, in veterinary medicine, NSAIDs also find use in management of severe pain, optimally in combination with an opioid. Although the beneficial effects of the febrile response usually outweigh the negative effects, NSAID inhibition of PGE 2 activity in the hypothalamus may provide symptomatic relief and improve appetite. In Europe, NSAIDs have been used in conjunction with antibiotics for treatment of acute respiratory diseases in cattle. They may reduce morbidity through their antipyretic and anti-inflammatory effects and prevent development of irreversible lung lesions.
Some, including aspirin , naproxen , and ibuprofen , are considered chondrotoxic, because they inhibit the synthesis of cartilage proteoglycans. Others, including carprofen and meloxicam , may be considered chondroneutral, or depending on dose, actually stimulate the production of cartilage matrix. The potential beneficial or deleterious effects of NSAIDs on chondrocyte metabolism remain to be clarified. A therapeutic area in which NSAID use may become important is in the treatment and prevention of cancer.
Epidemiologic studies in people show that aspirin use is associated with a significant reduction in the incidence of colon cancer. Newer evidence suggests that the therapeutic effect of NSAIDs on colon cancer is mediated by inhibition of COX-2, which may be upregulated in many premalignant and malignant neoplasms. In veterinary medicine, piroxicam has been shown to reduce the size of tumors such as transitional cell carcinoma in dogs.
Specific COX-2 inhibitors may prove useful as a primary or adjunctive therapy in the management of cancer. However, food can impair the oral absorption of some NSAIDs eg, phenylbutazone, meclofenamate , flunixin, and robenacoxib. Some parenteral formulations are highly alkaline eg, phenylbutazone and may cause tissue necrosis if injected perivascularly.
NSAIDs may also compete for binding sites with other highly protein-bound compounds, leading to some drug displacement; however, this displacement has little therapeutic consequence because it does not affect the concentration of the free drug. Consequently, their duration of action typically exceeds that predicted by elimination half-life. Most NSAIDs are biotransformed in the liver to inactive metabolites that are excreted either by the kidney via glomerular filtration and tubular secretion or by the bile.
Mavacoxib is an exception, mostly being excreted unchanged in the bile. Biotransformation and elimination half-lives vary significantly by species and in some cases by breed or strain, as is the case for some COX-2 inhibitors in Beagles , so it is not possible to safely extrapolate dosages from one species or animal to another.
Some NSAIDs, including naproxen , etodolac , and meclofenamic acid, undergo extensive enterohepatic recirculation in some species, resulting in prolonged elimination half-lives.
Many reactions to NSAIDs are dose-related and are typically reversible with discontinuation of therapy and supportive care. Vomiting is the most common adverse effect. GI ulceration is the most common life-threatening adverse effect. Loss of GI protective mechanisms results from inhibition of constitutive prostaglandins that regulate blood flow to the gastric mucosa and stimulate bicarbonate and mucus production. This disrupts the alkaline protective barrier of the gut, allowing diffusion of gastric acid back into the mucosa, injuring cells and blood vessels and causing gastritis and ulceration.
The enterohepatic recirculation of certain NSAIDs may result in high biliary concentrations that increase ulcerogenic potential in the gut. NSAID-induced GI bleeding may be occult, leading to iron-deficiency anemia, or be more severe, resulting in vomiting, hematemesis, and melena. Horses may develop oral, lingual, or colonic ulceration with accompanying signs of colic, weight loss, and diarrhea. Because TXA 2 inhibition causes prolonged bleeding, evaluation of buccal mucosal bleeding time is advised in animals for which surgery is anticipated.
Acetaminophen paracetamol administration in cats is associated with Heinz body anemia, methemoglobinemia, hepatic failure, and death. Bone marrow dyscrasias associated with phenylbutazone administration have also been reported. Animals with underlying renal compromise receiving NSAIDs could experience exacerbation or decompensation of their disease. It is important to maintain hydration and renal perfusion in animals receiving NSAIDs, especially those undergoing anesthesia or surgery and in horses with colic.
NSAID administration routinely induces mild hepatic changes characterized primarily by increases in liver enzymes without clinical signs or hepatic dysfunction. Rare reports of idiosyncratic reactions resulting in hepatic dysfunction or failure have been reported in people acetaminophen and others , dogs acetaminophen , carprofen, etodolac , and horses phenylbutazone.
Cytopathic hepatocellular injury, necrosis , cholestatic, and mixed histopathologic patterns of injury have been documented. The main subgroups of enolic acids are the pyrazolones phenylbutazone and the oxicams meloxicam , piroxicam. The newer coxib class of selective COX-2 inhibitors includes a diaryl-substituted pyrazole celecoxib and a diaryl-substituted isoxazole valdecoxib , both available for human use.
Four NSAIDs of the coxib class, deracoxib, firocoxib, robenacoxib, and mavacoxib have been introduced in veterinary medicine. By far the most widely used NSAID in people, aspirin is primarily used in veterinary medicine for relief of mild to moderate pain associated with musculoskeletal inflammation or osteoarthritis.
The salicylic ester of acetic acid, aspirin acetylsalicylic acid is available in several different dosage forms, including bolus for cattle , oral paste for horses , oral solution for poultry , and tablets for dogs. After PO administration, aspirin is rapidly absorbed from the stomach and upper small intestine.
After oral aspirin administration, salicylic acid is considered the main active substance in the systemic circulation. In addition, aspirin may irreversibly bind to COX-1 through acetylation of a serine residue near the enzyme active site. Depending on its route of administration, aspirin may have different pharmacologic effects. After absorption, both aspirin and salicylate are widely distributed through most tissues and fluids and readily cross the placental barrier.
Metabolism and elimination is via hepatic conjugation with glucuronic acid, followed by renal excretion. Cats, which lack glucuronyl transferase, metabolize salicylates slowly. In addition, salicylate metabolism is saturable and, if overexposure due to an aspirin overdose occurs, plasma salicylate elimination may follow a zero order and slower elimination kinetics. Because aspirin is not approved for veterinary use, definitive efficacy studies have not been performed to establish effective dosages.
Adverse effects are common after aspirin administration and appear to be dosage dependent. Vomiting and melena may be seen at higher doses. Aspirin overdose in any species can result in salicylate poisoning, characterized by severe acid-base abnormalities, hemorrhage, seizures, coma, and death. Acetaminophen paracetamol is a para-aminophenol derivative with analgesic and antipyretic effects similar to those of aspirin , but it has weaker anti-inflammatory effects than does aspirin and other NSAIDs.
Acetaminophen does not inhibit neutrophil activation, has little ulcerogenic potential, and has no effect on platelets or bleeding time. Dose-dependent adverse effects include depression, vomiting, and methemoglobinemia. Use in cats is contraindicated because of their deficiency of glucuronyl transferase, which makes them susceptible to methemoglobinemia and centrilobular hepatic necrosis. One of the earliest NSAIDs approved for use in horses and dogs, phenylbutazone PBZ is a pyrazolone derivative available in tablet, paste, gel, and parenteral formulations.
When given PO, PBZ adsorbs to hay in the diet, to then be released during fermentation in the hindgut. Although this potentially may reduce GI absorption and bioavailability, the clinically relevant effect is a delay in absorption.
PBZ is metabolized by the liver to several active oxyphenbutazone and inactive metabolites, which are excreted in urine. Laminitis is treated initially with injectable PBZ at dosages up to 8. Because the therapeutic index for PBZ is relatively narrow PBZ exhibits zero order metabolism , the dosage should be adjusted to the minimum possible to maintain comfort and avoid toxicity.
GI effects eg, anorexia and depression are the most frequent adverse effects associated with PBZ. Ulcers may develop in the mouth, stomach, cecum, and right dorsal colon. The ulcerogenic potential of PBZ in horses is greater than that of flunixin and ketoprofen.
In dogs, PBZ has been associated with bleeding dyscrasias, hepatopathies, nephropathies, and rare cases of irreversible bone marrow suppression. Meclofenamic acid is a fenemate anthranilic acid NSAID available for horses as a granular preparation and for dogs as an oral tablet. The recommended dosage is 2.
The onset of action is slow, requiring 2—4 days of dosing for a clinical effect. It is used for fever, postoperative pain, and acute and chronic inflammatory conditions in cats, dogs, cattle, and pigs. In the USA, the nicotinic acid derivative flunixin as the meglumine salt is approved for use in horses as PO and parenteral formulations. The recommended dosage is 1. Elimination is primarily by renal excretion.
Flunixin is effective for the treatment of visceral pain associated with colic in horses. It is also used to reduce the inflammatory-mediated hemodynamic response to endotoxin, although it is unlikely to reduce mortality associated with endotoxemic shock. The dosage recommended in horses is 1. Chronic administration of flunixin to dogs may result in severe GI ulceration and renal damage. Flunixin is not marketed in the USA for dogs, but it is approved in Europe and other countries.
An injectable formulation is also available in the USA and Europe.