Today's Veterinary Practice

MAY-JUN 2014

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| aCUTe PaIN IN CaTS: TreaTmeNT wITh NSaIDS 26 Today's Veterinary Practice May/June 2014 tvpjournal.com These 2 formulations should be usable and approved for use, interchangeably. For exam- ple, an injectable formulation facilitates both perioperative and immediate postoperative pain management, when it may be difficult or impossible to medicate animals orally. However, an oral formulation is beneficial for postoperative pain management upon dis- charge and long-term chronic pain manage- ment because it allows the drug to be admin- istered in the home environment. For cats specifically, palatable oral formu- lations facilitate administration and compli- ance—important components of pain man- agement. Cats are selective about what they eat, and it is difficult to hide an unpalatable pill or medication in food or a treat, as is often done with dogs. If the cat won't willing- ly take the medication, it must be restrained and dosed. An NSAID formulation should be easily titrated, if necessary, and/or have an easy-to- determine dose. In tablet form, it should have a wide dose range that allows for administra- tion of whole tablets, rather than fractioning tablets in order to stay within the therapeu- tic range. Figure 2. This figure illustrates the difference between 4 exam- ples of NSAIDs, each dosed every 24 hours. All examples show tissue selectivity but have different half-lives. NSAID 1 has a short half-life, and is cleared quickly from the central compartment (blood), thus, theoretically limiting exposure of noninflamed tis- sues. In contrast, NSAID 4 has a relatively long half-life, exposing noninflamed tissues to the NSAID for most of the 24-hour peri- od. The clinical significance of this difference between individual NSAIDs is not known. CONCEPT OF TISSUE SELECTIvITy Tissue selectivity is a concept that involves the highly protein-bound nature of NSAIDs and the acidic environment of inflammation. During the process of inflammation, there is extravasation, or leakage, of protein from blood vessels into the extracellular environment. Since NSAIDs are known to be "highly protein bound" at normal physiological pH, if an NSAID has been administered, it will be bound to this protein. The acidic extracellular environment of the inflamed tissue causes dissociation of the drug from the protein due to the low pK a — acid dissociation constant—of the drug. After the drug dissociates from the protein, the increased free fraction of the active drug facilitates its movement into the cells where it then remains due to a phenomenon called ion trapping (passive movement of the drug into cells due to differences in pH between the intracellular and extracellular environment). 13 This theory explains why NSAIDs may have a prolonged presence in inflamed tissue, while having a more rapid clearance from the central compartment—blood stream and other noninflamed organs. 14 • The ideal NSAID should, therefore: » Spare COX-1 as much as possible » Inhibit COX-2 sufficiently for efficacy against pain and inflammation » Spare enough COX-2 to allow it to function in nor- mal everyday processes. 2. Provides Targeted Action Current thinking suggests that an ideal NSAID should have prolonged action at the site of inflammation and a short half-life in the central compartment, limiting exposure of normal, noninflamed, nonpainful tissues (Figure 2). This is because, given the broad distribu- tion and role for prostaglandins throughout the body, if prostaglandins needed for normal, everyday func- tions are inhibited, there is potential for unwanted side effects. Dr. Kay Brune, a leader in the field of NSAID research, has described a theory of "targeted tissue selectivity" that is a combination of enzyme specificity (selective COX-2 inhibition) and tissue selectivity, which, he has argued, might result in better toleration of the drug, while main- taining efficacy (see Concept of Tissue Selectivity). 13 3. Administered with Ease & Accuracy Ideally, for optimal practical administration, NSAIDs should be: • Available in an injectable and palatable, oral formula- tion • Easily titrated and have an easy-to-determine dose. Green arrow indicates the difference between the time in the central compartment and time in inflamed tissue. The clinical significance of this difference between individual NSAIDs is not known. TVP_2014-0506_FelinePainMgmt (Part 2).indd 26 5/23/2014 11:23:09 AM

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