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NSAID Toxicity in Horses

Description
NSAID toxicity is another important subject, because we (veterinarians, owners) cause it! Excessive doses, or labelled doses in a dehydrated animal, will reduce renal medullary PGE synthesis and result in decreased blood flood with parenchymal damage in the medulla. Renal papillary necrosis is the classic lesion. Affected horses often will have concurrent GI disorders, but we have seen many horses with only renal involvement. It may be that renal lesions occur at a relatively lower doses than GI lesions





Aspirin

Additional information


Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
The nonsteroidal anti-inflammatory drugs are among the most widely used drugs in veterinary medicine. Some NSAIDs have valuable therapeutic properties, and some have a great potential for toxicity. Due to their potential for misuse, a thorough knowledge of their clinical pharmacology is important for effective use.

Pharmacology
The NSAIDs commonly used in horses are:
  • aspirin
  • phenylbutazone
  • dipyrone
  • flunixin meglumine
  • meclofenamic acid
  • ketoprofen



    All NSAIDs are weak acids and highly bound to proteins in the blood. Therefore, they are well absorbed from the stomach, but then because of protein binding, most of the drug remains in the blood. Only low levels of NSAIDs are found in normal tissues and joint fluid. In damaged tissues and joints however, NSAID levels increase to therapeutic levels because of the increased blood flow and the leaking of blood fluids from damaged blood vessels.

    Mechanism of action
    The NSAIDs block the cyclooxygenase enzyme, interrupting formation of thromboxane, prostacyclin and the prostaglandins from arachidonic acid. This results in antipyretic action (reduces fever), mild pain relief, anti-inflammatory effects and inhibition of platelet clumping. Recent research has also shown that some of the NSAIDs act on pain receptors in the central nervous system and block pain in the same way as drugs like morphine. NSAIDs are also thought to alter immune system responses and suppress inflammatory mediators other than the cyclooxygenase products.

    Drug interactions
    The occurrence and potential hazards of drug interactions must be considered with therapeutic use of the NSAIDs. In general, any two NSAIDs administered together will be additive in their effect. Since all NSAIDs act by the same mechanism of cyclooxygenase inhibition, higher dose of a single NSAID should produce the same response. Because all of the NSAID drugs are highly bound to blood proteins, caution must be used when other highly protein bound drugs are administered. Competition for protein binding sites can result in dramatic increases in free drug available for pharmacological action and cause toxicity. Some of the effects of the diuretic, furosemide (Lasix®), are dependent on normal prostaglandin levels. Concurrent administration of furosemide and NSAIDs may reduce the efficacy of furosemide.

    Adverse effects
    The adverse effects of the NSAIDs are related to blocking cyclooxygenase in tissues where prostaglandins are beneficial and protective. Reduction in protective prostaglandins results in constriction of blood vessels and tissue damage in the kidney and reduction in blood flow and protective mucus production in the gastrointestinal tract resulting in ulcers, colic and diarrhea. NSAIDs have a higher incidence of toxicity in foals because their kidney function is not fully developed. When it is necessary to use NSAIDs in foals, they should be administered at the lowest possible doses. NSAIDs should be administered very cautiously to dehydrated horses. Blood concentrations will be greater than normal in the dehydrated horse and are more likely to cause toxicity. Treatment of NSAID toxicity is intensive and mainly supportive. The hypoproteinemia that results from loss of blood proteins into the ulcerated gastrointestinal tract can be corrected with intravenous infusions of plasma. Commercial sources of equine plasma are available, but this therapy is extremely expensive in adult horses. The fluid and electrolyte losses that accompany the diarrhea are managed with commercially available intravenous fluids. Broadspectrum antibiotics are indicated when there is evidence of bacterial septicemia (blood infection). Colic pain must be managed with opiod analgesics, as additional NSAID therapy must be avoided. Anti-ulcer medications may be beneficial and speed recovery. Surgical removal of damaged sections of intestine may be necessary in some cases. Recovery is usually slow and in severe cases the prognosis is always guarded.

    Aspirin
  • Pharmacology Aspirin irreversibly binds to cyclooxygenase in platelets and other cells and prevents the conversion of arachidonic acid to prostaglandins, thromboxanes and prostacyclin. The action of most of the other NSAIDs on platelet cyclooxygenase is reversible, therefore, aspirin has the greatest anti-clotting activity of the NSAIDs. Aspirin is only available in oral formulations as boluses containing 60 or 240 grains of aspirin or as a powder. Aspirin is well absorbed from the stomach, and high concentrations are attained in the liver, heart, lungs, kidneys and blood. Aspirin is partially converted in the blood and by the liver to salicylic acid, and both are rapidly excreted by the kidneys into the urine. Salicylic acid is a natural component of horse urine, but the normal concentration is quite low. Drug testing for aspirin requires accounting for this natural production. Because of the irreversible binding to cyclooxygenase, the anti-coagulant activity of aspirin lasts far longer than its antipyretic (fever reducing), anti-inflammatory and analgesic (pain relieving) activity. A single dose of20 mg/kg will prolong bleeding time in horses for 48 hours. Therefore, an anti-clotting aspirin dosage is 10 mg/kg every 2 to 3 days, or 20 mg/kg every 4 to 5 days.
  • Uses/indications Aspirin has the weakest anti-inflammatory and analgesic (pain relieving) activity of the NSAIDs in horses, so it is rarely used in horses for inflammatory conditions. Its anti-clotting action is useful in treating conditions in the horse that involve damage to blood vessels and the subsequent formation of blood clots, such as laminitis, verminous (parasite) colic, recurrent uveitis (periodic ophthalmia or "moon blindness"), and endotoxemia.
  • Adverse effects The most common adverse effect of aspirin therapy is stomach or intestinal irritation with blood loss. Because of its effect on blood clotting, aspirin therapy should be discontinued one week prior to the horse having any surgery. If used in pregnant mares, aspirin may delay foaling or increase bleeding at foaling.

    Phenylbutazone ("bute", PBZ)
  • Pharmacology Phenylbutazone (PBZ) has analgesic (pain relieving), anti-inflammatory, and antipyretic (fever reducing) activity from inhibition of cyclooxygenase. It is available in many intravenous and oral formulations (powder, paste, gel, tablets). The injectable formulation must be given by careful intravenous injection, otherwise it causes severe tissue damage if given intramuscularly or subcutaneously. Following oral administration, PBZ is well absorbed, but time it takes to reach peak blood levels is delayed by feeding the horse, as the PBZ sticks to feed particles. In the blood, greater than 99% of the PBZ is carried bound to blood proteins. Phenylbutazone is converted by the liver to oxyphenbutazone, a metabolite with the same action as PBZ, but removed slower from the body than PBZ. The capacity of the liver to process PBZ becomes overwhelmed at relatively low drug doses. Therefore, increasing doses of PBZ can easily result in toxicity. In the horse, the therapeutic effect of PBZ lasts for more than 24 hours, due to the slow excretion of the oxyphenbutazone metabolite. PBZ and oxyphenbutazone will cross the placenta and are excreted in mare's milk.
  • Uses/indications Phenylbutazone is used extensively in horses for a variety of common musculoskeletal disorders including navicular disease, laminitis, osteoarthritis and degenerative joint disease. It is economical and many brands are available. The use of PBZ in performance horses is very controversial, and it is highly regulated by individual performance associations. It is less effective in the therapy of colic and endotoxemia than flunixin meglumine (Banamine®). Phenylbutazone has less anti-clotting activity than aspirin and clinical use is not associated with increased bleeding. An initial dose of 4.4 mg/kg every 12 hours for the first day of therapy is followed by 2.2 mg/kg once a day for several days. Due to drug accumulation from the slow excretion of oxyphenbutazone, long-term PBZ therapy for chronic lameness conditions should be on an every other day basis with the lowest effective dose.
  • Adverse effects Gastrointestinal effects are the most important adverse effects of PBZ therapy in horses. Clinical signs include loss of appetite, depression, colic, weight loss, ventral edema, hypoproteinemia (low blood protein), and diarrhea. Hemorrhages and ulcers may occur in the mouth, esophagus, stomach, cecum and right dorsal colon. These toxic effects are related to the dose of PBZ given. Horses that receive less than 0.4 g/l00 lbs of body weight per day for 4 days (4 grams to a 1000 lb horse) or 0.1-0.2 g/100 lbs of body weight per day for up to 50 days remain clinically normal. Horses that receive more than 0.4 g/100 lbs of body weight per day for 4 days develop toxicity. In a study, horses that received approximately 7 g of PBZ developed gastrointestinal ulcers within 24 hours. Ulcer formation is thought to be predominantly due to PBZ-induced blood vessel constriction to the mucosal lining of the gastrointestinal tract. PBZ also causes kidney damage from inhibiting the prostaglandins that maintain kidney blood flow. Because of its mechanism of action against prostaglandins, PBZ toxicity occurs whether the drug is administered intravenously or orally. Dehydration contributes to the toxicity potential of PBZ by reducing the blood flow to the kidney, therefore it is very important that horses on PBZ therapy have adequate water intake.
  • Since normal liver function is required for conversion and elimination of PBZ and oxyphenbutazone, liver disease can result in toxicity even when PBZ is administered at recommended doses.
  • Because PBZ can alleviate lameness in horses for several days following therapy, it may be used to disguise lameness for the purpose of soundness examinations or for competitive purposes.
  • Chronic, low-dose PBZ has been given to broodmares with no obvious effect on their ability to conceive or carry a foal to term. However, its use should be kept to a minimum in pregnant mares.
  • PBZ may interact with other highly protein bound drugs such as phenytoin, warfarin, and other anti-inflammatory agents and result in toxicity. Protein bound drug is not available to tissues for pharmacological action. When a drug is 99% plasma protein bound, only 1% of drug is available to tissues for effect. If another highly protein bound drug is administered simultaneously, that has a greater affinity for the protein binding sites, a small change in the degree of protein binding will result in a dramatic change in drug available for action. This explains the well known interaction between warfarin (an anti-clotting treatment for navicular disease) and PBZ. With the administration of PBZ to a horse on warfarin therapy, the PBZ displaces some of the warfarin from protein binding sites. If the amount of protein binding of warfarin is reduced to 98%, then the concentration of free warfarin effectively doubles (to 2%) and can cause a bleeding crisis in the horse.
  • Phenylbutazone competes for the same cellular binding sites as thyroid hormone. Treating horses for just 5 days causes a significant decrease in baseline thyroid hormone (T3 and T4) concentrations. Treated horses have a greater than normal response to injection with thyroid stimulating hormone.

    Dipyrone (Austin, Langford, P.V.L.)
  • Pharmacology The pharmacology of dipyrone has not been well investigated in horses. Dipyrone is thought to act similarly to other NSAIDs by inhibiting cyclooxygenase. Dipyrone is available as a 50% solution (500 mg/ml), and can be administered IV, IM or SC to horses.
  • Uses/indications Dipyrone has analgesic (pain relieving), antipyretic (fever reducing), and slight anti-inflammatory properties. It reportedly has antispasmodic activity on bradykinin-induced spasms of the gastrointestinal tract (spasmodic colic), but does not have the potency of flunixin meglumine (BanamineTM) for other types of colic. Dipyrone does not affect normal intestinal motility. Most veterinarians feel that other analgesic agents are more effective than dipyrone in the therapy of equine colic or pain.
  • Adverse effects High doses or chronic therapy with dipyrone may result in damage to the horse's bone marrow; manifested by abnormal blood cell production. Other adverse reactions include gastrointestinal upset, pain at the injection site, skin reactions, hemolytic anemia, tremors, and anaphylactic (allergic) reactions. It should not be administered to horses with blood or bone marrow problems. It should not be administered concurrently with acepromazine, phenylbutazone, or barbiturate anesthetics.

    Flunixin Meglumine (Banamine®, Schering Plough Animal Health)
  • Pharmacology Flunixin meglumine is a very potent inhibitor of cyclooxygenase that is available in injectable, oral paste and oral granule formulations. Flunixin is rapidly absorbed following oral administration, and peak blood levels occur within 30 minutes. The onset of anti-inflammatory and analgesic action is within 2 hours and duration of action can be up to 36 hours. Like other NSAIDs, flunixin is highly protein bound. Flunixin is eliminated by the kidneys, and can be measured in urine for 48 hours after a single dose. Flunixin's pain relieving effect lasts long after the concentrations in the blood have become negligible. The long duration of pain relief appears to be due accumulation in inflamed tissues and to interaction of flunixin in the central nervous system with opiod receptors in a manner similar to morphine.
  • Uses/indications Flunixin is used in horses for a variety of inflammatory and painful conditions: colic, colitis, exertional rhabdomyolysis ("tying up"), endotoxic shock, respiratory disease, eye injuries and diseases, general surgery, laminitis, and other musculoskeletal disorders. Extensive research substantiates the efficacy of flunixin over other NSAD)s in the therapy of endotoxic shock in horses. Flunixin may be used to prevent abortion in endotoxemic pregnant mares or after attempting to "crush" a twin. The recommended dose is 1.1 mg/kg of body weight once daily, but your veterinarian may need to increase the frequency of this dose in very painful conditions such as colic. Low dose therapy with flunixin, at one quarter the label dose administered three to four times a day, has anti-endotoxic effects without masking signs of colic pain or causing toxicity. Conversely, extremely high doses of flunixin may mask signs of surgical colic pain and prevent the veterinarian from recognizing the need for surgical intervention. Flunixin does affect normal platelet function, but blood clotting failure is not seen with clinical use and administration prior to surgery is safe.
  • Adverse effects Flunixin has similar adverse effects as PBZ, but appears somewhat less toxic than PBZ in horses. High doses can result in loss of appetite, depression, and gastrointestinal tract ulcers. In normal foals, the label dose of flunixin administered for 5 days did not produce adverse effects, but six times the label dose resulted in gastrointestinal ulcers. In another study, where foals were administered flunixin at the label dose for 30 days, all treated foals developed gastric ulcers. At three times the label dose given for 7 days, approximately 50% of normal horses or ponies will develop gastric ulcers.
  • Intramuscular injections of flunixin have been incriminated in cases of fatal clostridial myositis (bacterial infection of the muscle) in horses. When injected into muscle, the drug's formulation causes slight tissue damage and an anaerobic (without oxygen) environment. On rare occasions, a clostridial organism spore is picked up as the needle passes through the horse's haircoat and is injected into the tissue. In the anaerobic environment, the spore becomes activated and proliferates, releasing toxins and causing massive muscle damage. If not treated promptly and aggressively, clostridial myositis is rapidly fatal.

    Meclofenamic Acid (Arquel®; Vetrepharm)
  • Pharmacology Meclofenamic acid is a very palatable oral granule used in horses for the treatment of inflammatory musculoskeletal conditions. This drug has not been extensively researched in veterinary medicine. Feeding prior to dosing may delay absorption of meclofenamic acid from the horse's stomach.
  • Uses/indications Meclofenamic acid is dosed in horses at 2.2 mg/kg of body weight given as a 20 grams of Arquel® granules to a 1000 lb horse once a day in the feed. It is an unusual NSAID in that its anti-inflammatory and analgesic action can take 36-96 hours to develop. Clinical efficacy can be seen for days once therapy is discontinued. Repeated daily dosing does not result in drug accumulation, therefore this is a useful drug for chronic inflammatory conditions such as navicular disease or bone spavin. Many horses can be maintained comfortably with twice weekly dosing without side effects. In clinical studies, researchers found clinical improvement in the lameness of 2/3 of treated horses, but found it difficult to predict which horses would respond to meclofenamic acid.
  • Adverse effects At normal doses, some decrease in blood protein concentrations may be seen. Doses of 68 times the label dose result in toxicity, including mouth ulcers, loss of appetite, depression, edema and weight loss. When administered at the label dose chronically to stallions and pregnant mares, no toxic effects were seen.

    Ketoprofen (Anafen®; Rhone Merieux, Canada Inc)
  • Pharmacology Ketoprofen is a propionic acid NSAID. Initial work suggested that ketoprofen had an inhibitory action on lipoxygenase in addition to cyclooxygenase inhibition. However, clinical work in horses and other species has shown that ketoprofen only blocks the production of cyclooxygenase derived mediators of inflammation. Ketoprofen and its active metabolites persist in inflamed tissues at concentrations higher than blood concentrations, so the anti-inflammatory effects of ketoprofen are not related to its concentration in the blood. Ketoprofen is rapidly eliminated from the blood, therefore kidney-damaging drug accumulation does not occur. The maximum anti-inflammatory effects of ketoprofen occur at 12 hours after a dose and last for 24 hours. Ketoprofen is available as 100 mg/ml solution for intravenous injection at a dose of 1 mg/kg.
  • Uses/indications Advantages claimed for the use of ketoprofen in horses include inhibition of bradykinin and inhibition of both cyclooxygenase and lipoxygenase pathways. This anti-lipoxygenase effect is seen in laboratory studies, but has not been demonstrated in actual studies in live horses. A cartilage-protective effect that has been seen in cartilage cultures in the laboratory has also not been demonstrated in live horses. It is recommended for musculoskeletal injuries, where a single dose gives good pain relief and anti-inflammatory activity for 24 hours.
  • Adverse effects Ketoprofen does not appear to be substantially different from flunixin meglumine for clinical use in horses, but appears to be less likely to cause gastrointestinal ulcers than other NSAIDs. In a small toxicity study in horses, ketoprofen produced fewer gastrointestinal lesions than treatment with flunixin meglumine or phenylbutazone. At doses many times the label dose, clinical signs of ketoprofen toxicity are similar to those seen with other NSAID toxicities.
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