Nonsteroidal anti-inflammatories in cats (Proceedings)
Nonsteroidal anti-inflammatory drugs have been used for centuries for the control of fever and pain. Until recently,the basis for selection of a NSAID has not been well based. Few differences existed among drugs in either efficacy or safety. With the advent of the new "super aspirin", the selection might now be more accurately based on safety without loss of efficacy. However, the cat as a species represents a therapeutic challenge when trying to use NSAIDs safely. Nonsteroidal anti-inflammatory drugs block the first step of prostaglandin synthesis by binding to and inhibiting cyclooxygenase This action is both dose and drug dependent. The pharmacologic effects of this class of drugs and the relative dose associated with the effect include (antithrombotic, especially aspirin) <<< antipyresis < analgesia < control of inflammation.
The role of PGs in normal physiology might best be understood by considering them as protective in nature. Their formation is mediated by one of at least two isoforms of cyclooxygenases. An inducible form (COX-2_ is measured following endotoxin stimulation (induction) of PG in macrophages. The constitutive form is characterized by baseline activity; designated COX-1, it is generally measured as thromboxane B2 synthesis from platelets. These or similar tests are used to generate a COX1:COX2 ratio which indicates the concentration of the NSAID that is needed to to inhibit 50% of the activity of either enzyme. A ratio > 1 indicates COX 2 is more easily inhibited than COX-1, often interepreted as a safer drug. However, these ratios must be studied in the species of interest and even then should serve only for screening purposes. Currently, one veterinary drug is approved for use for cats in the US (compared to 5 for dogs), although several others have been used effectively. What is not clear is which of these drugs prefer COX-2 to COX-1 in cats; to date, it appears that a ratio in cats has been reported only for carprofen (similar to dogs). NSAIDS with data addressing use specifically in cats include piroxicam, ketoprofen and carprofen. Tepoxalin (Zubrin®), the newest NSAID approved for use in dogs, is a "dual inhibitor", targeting both COX and LOX, thus targeting prostaglandins and leukotrienes. Some data exists to address its potentially safe use in cats.Cox 1 versus Cox 2: Physiology and Pathology
In general, inhibition of COX-1 is responsible for efficacy whereas inhibition of COX-2 is responsible for side effects. However, strict adherence to this simplistic approach will lead to therapeutic failure and increased morbidity with NSAID use. Although COX-1 does indeed appear to be the predominant constitutive enzyme protecting the body, both COX-1 and COX- are constitutively expressed in many tissues. Further, COX-1 does appear to have some role in inflammation. Some examples of the diverse role of PGs include the following. Central Nervous System: In addition to pain, COX-2 has an important role in the pathogenesis of Alzheimer's Disease (AZD), and acute brain injury. Pain: PGs have been implicated in causing increased pain perception (allodonia) in damaged compared to normal tissues. Induced COX-2 PGE as been associated with hyperalgesia (exaggerated response to pain) in either the spinal cord (primary hyperalgesia ) or at nociceptors in peripheral tissues (secondary hyperalgesia and central sensitization, manifested as a change in excitability threshold. Through COX-2, prostaglandins influence other CNS neurotransmitters (eg, glycine inhibition or glutamate stimulation) or other receptors (eg, NMDA). PGs also appear to mediate the anorexia and lethargy associated with chronic pain. Gastrointestinal tract: Both COX-1 and COX-2 are constitutively expressed in the GI tract. Although COX-1 provides the major role in the protection of the GI tract, induction of COX-2 is important to healing of GI damage. Healing: The application of PGE-2 facilitates bone healing in experimental animals; 4 weeks of ibuprofen (16%) or rofecoxib (Vioxx®; 87%) compared to placebo (0%) led to mal-union in rats with experimentally-induced fractures. Cardiovascular Disease: Platelets contain thromboxane synthetase, which catalyzes the formation of thromboxane from arachidonic acid. Thrombosis reflects platelet aggregation and vasoconstriction. The formation of a thrombus is kept "in check" by the presence of prostacyclin synthetase in vascular endothelial cells. This enzyme catalyzes metabolism of arachidonic acid to prostacyclin (PGI2), a vasodilatory and platelet inhibiting prostaglandin endproduct. However, whereas TXA2 is associated with COX-2, prostacyclin synthetase is associated with COX-1. The preferential inhibition of COX-2 may allow thrombus formation to go unchecked, increasing the risk of thromboembolic disorders. Thus, care must be taken when using these drugs in patients with hypertrophic cardiomyopathy. Kidney: In the kidney; both COX-1 and 2 are constitutively expressed. Both are formed in the macula densa of humans and animals, but COX-2 may have a more important role than COX-1. In (nonhuman) animals, inhibition of COX-2 causes sodium and potassium retention in salt depleted, but not normal, animals. However, in humans, COX-2 appears to influence renal vasculature and podocytes. Lungs: The role of PGs in the lungs is less than that of leukotrienes; however, inflammatory diseases, such as asthma, are associated with smooth muscle proliferation which is inhibited by COX-2. Thus, like the GI tract, COX-2 appears to have a protective role in the diseased lung. Note that with older NSAIDs, inhibition of COX resulted in shunting of AA to LOX and increased production of leukotrienes. While this is not longer an issue in human medicine, the issue may remain in cats until the role of COX inhibition is clarified for each of the drugs. As such, NSAIDs should be used only with caution in cats with asthma. An exception might be tepoxalin. Cancer: COX-2 increases markedly in a variety of soft-tissue tumors in humans and in transitional cell carcinoma in dogs (Knapp 2004). These studies suggest that benefits of NSAIDs in cancer may reflect inhibited COX-2. Depending on the model, inhibition of COX-2 associated with tumors reduces cell proliferation, increases apoptosis, and reduces metastasis. Inhibitors may also enhance anti-tumor effects of radiation, although toxicity is increased. However, at least for NSAIDs, GI toxicity is also increased when combined with antimetabolite anticancer drugs, presumably reflecting a combined toxic effect on the GI tract.