Nonsteroidal Anti-inflammatory Drugs

CHAPTER2 Nonsteroidal Anti-inflammatory Drugs



Anthony T. Blikslager


The term nonsteroidal anti-inflammatory drug (NSAID) literally refers to an anti-inflammatory drug that is not a steroid, but it has become synonymous with a drug that has cyclooxygenase (COX) inhibitory activity. This enzyme converts arachidonic acid to the intermediary prostanoid prostaglandin H2 (PGH2), after which local tissue synthases, such as prostaglandin E (PGE) synthase, convert PGH2 to a prostanoid that has activity by interacting with cellular receptors. Overall, the name of the drug class and veterinarians’ impression of what prostaglandins do would suggest a straightforward anti-inflammatory effect. However, scientific knowledge about the activity of COX and the prostanoids has dramatically changed in the last decade and is worth considering so that a more complete understanding of NSAIDs and appropriate patient care can be achieved.


The first major step in understanding the mechanism of NSAIDs was the discovery that aspirin inhibits COX. However, at that time (i.e., the early 1970s), it was assumed there was one COX enzyme. It is now known that there are multiple COX isoforms, including COX-1, COX-2, and COX-3. COX-1 is called a constitutive enzyme in most tissues and most species because it is always present and does not seem to be affected by inflammation. It is therefore credited with the positive effects of the COX-prostanoid cascade, including protection of important organ systems, such as the gastrointestinal tract and the kidneys. On the other hand, COX-2 is called inducible because it is not typically expressed unless it is upregulated by pro-inflammatory stimuli. The classic example of a pro-inflammatory stimulus in equine medicine is lipopolysaccharide (LPS), or endotoxin, which stimulates an inflammatory cascade that results in expression of COX-2. However, the view that COX-1 is beneficial and COX-2 is pro-inflammatory is an oversimplification, as demonstrated by adverse events noted in people taking COX-2 inhibitors, leading to the voluntary withdrawal of rofecoxib (Vioxx) from the market, and gastric adverse events in dogs administered COX-2 inhibitors. Nonetheless, it is generally true that COX-2 inhibitors have a greater safety profile, particularly on unintended target organs such as the gut, compared with nonselective inhibitors. Therefore, COX-2 inhibitors may prove to be advantageous in equine patients with conditions such as lameness or colic in providing analgesia and reduction of inflammation while minimizing unwanted side effects.


The NSAIDs that are currently available to equine practitioners, including phenylbutazone, flunixin meglumine, and ketoprofen inhibit all COX isoforms. Therefore, differences in efficacy of these NSAIDs for select diseases are difficult to reconcile with their mode of action. In other words, there are no data from well-designed clinical trials to substantiate a greater degree of efficacy for phenylbutazone when treating lameness or for flunixin meglumine when treating colic. However, practitioners believe they can detect differences in the efficacy of the available NSAIDs, which may ultimately be explained by a more thorough understanding of the NSAIDs. For instance, aspirin irreversibly alters the active site of COX-1, resulting in a long-term effect of aspirin well beyond its half-life in platelets, which express only COX-1. Recently, it was shown that aspirin also irreversibly alters the COX-2 active site, resulting in diversion of the arachidonic acid cascade toward anti-inflammatory lipoxins. As far as other NSAIDS are concerned, some do more than simply inhibit COX, including inhibition of pro-inflammatory enzymes involved in the nuclear factor kappa B (NFκB) cascade, which is triggered by endotoxin. The important lesson to learn from all this new research is that NSAIDs are more complex compounds than originally thought, and discovery of new mechanisms of action of select NSAIDs will likely alter practitioners’ choices in the future.

Related posts:

  1. Protecting Yourself with Medical Records
  2. Systemic Chemotherapy for Oncologic Diseases
  3. Coagulopathies
  4. Nutritional Factors in Developmental Orthopedic Disease

Stay updated, free articles. Join our Telegram channel
Tags:
May 28, 2016 | Posted by in EQUINE MEDICINE | Comments Off on Nonsteroidal Anti-inflammatory Drugs

Full access? Get Clinical Tree
Get Clinical Tree app for offline access