A review of how anti-inflammatories work and different available classes
The Arachidonic Acid Cascade
Every cell in the body is surrounded by a phospholipid bilayer (cell membrane) that is made of polyunsaturated fats. Arachidonic acid (AA) is part of the phospholipid bilayer; it is an omega 6 polyunsaturated fat. If a cell is broken down, either due to normal cell turnover or cell injury, phospholipase A2 causes a release of AA from the cell membrane. The AA molecule is then broken down by one of 2 pathways that ultimately generate two groups of molecules: prostanoids and leukotrienes.
The enzyme cyclooxygenase 1 (COX-1) converts AA to 5 active prostanoid molecules: Thromboxane (TXA), PGD2, PGI2, PGF2a, and PGE2. The enzyme COX-2 converts AA to PGI2 and PGE2.
PGE2 is considered to be the most important prostanoid involved in pain and inflammation and is the primary target of NSAIDs. While PGE2 is an important mediator of pain and inflammation, it also has necessary and beneficial properties, particularly in the stomach and kidney.
Both COX-1 and COX-2 enzymes are involved in homeostatic functions throughout the body. However, the COX-2 enzyme is up-regulated during injury and inflammation. In other words, tissue injury leads to excessive production of AA and thus the COX-2 enzyme is induced to metabolize surplus AA.
There are 3 lipoxygenase (LOX) enzymes that convert AA to leukotrienes, including LTB2 and LTE4. The leukotrienes are involved in inflammation, in particular, vascular permeability and neutrophil recruitment and activation.
How does each class of anti-inflammatory work?
Corticosteroids
Corticosteroids inhibit the enzyme PLA2, thus acting up-stream in preventing the metabolism of AA. Corticosteroids prevent the generation of prostanoids and leukotrienes and have broad anti-inflammatory action, yet, they also inhibit the production of many homeostatic AA metabolites.
The administration of oral steroids for the treatment of pain and OA can be thought of as dropping a bomb on the AA pathway—it is the least targeted approach possible with the most far-reaching negative effects. (Steroids do remain an important treatment option for several medical conditions, and intra-articular steroids are not associated with the same widespread effects as oral products LINK to IA)
Aspirin: Non-selective COX- inhibitor
Salicylic acid is a natural product derived from certain plants such as willow bark and meadowsweet, and its medicinal properties of pain relief and fever reduction have been used for centuries. Aspirin, or acetylsalicylic acid, is a synthetic drug made from salicylic acid and was first produced in Germany in the 1850s and commercialized by Bayer in the 1890s. However, it wasn’t until the 1970s that aspirin’s mechanism of action was discovered.
Aspirin irreversibly binds to the COX-1 enzymes and inhibits the formation of all prostanoids. While aspirin is effective at reducing pain and inflammation, the significant adverse effects are well-recognized, in particular, gastrointestinal irritation/ ulceration and reduced clotting. Irreversible inhibition of TXA by aspirin leads to reduced platelet aggregation that lasts up to 10 days following a single administration. This property can be useful therapeutically but should also be recognized as a potentially significant unwanted side effect of aspirin administration.
If steroids are a bomb-approach to pain management, indiscriminate inhibition all PG and TXA production by aspirin can be considered the grenade approach. Pharmacologic advancements have led to more selective therapies, therefore, aspirin is not recommended as a treatment for OA in dogs.
COX-2 selective and preferential NSAIDs
“Traditional” NSAIDs, such as carprofen, meloxicam, firocoxib, and deracoxib all work by inhibiting the COX 1 and 2 enzymes and decreasing the production of PGE2 (along with other prostanoids). These drugs were developed to overcome the limitations of aspirin and other non-selective NSAIDS (eg, ketoprofen) by preferentially inhibiting COX 2 over COX 1 (each drug has a different COX1/2 profile).
All of these products are considered safer than aspirin or other non-selective NSAIDs, yet they do still have the potential to cause adverse effects in the stomach and kidney. Although the true incidence of side effects with all NSAIDs currently remains unknown, it is believed to be very low compared to the millions of doses administered.
There are several precautions to take when prescribing NSAIDs that will decrease the chance of side effects (LINK to top of this article). While the potential for adverse effects should not be ignored, the proven efficacy in reducing pain makes NSAIDs part of the foundation of OA management at this time.
Piprants: EP4 Antagonists
In 2016, grapiprant (Galliprant) was approved by the FDA for the treatment of OA in dogs. Galliprant belongs to a new class of NSAIDs called Piprants and the mechanism of action is different than all of the other NSAIDs on the market.
Piprants are prostaglandin receptor antagonists, meaning that they block the action of an individual prostanoid (TXA, PGD2, PGI2, PGF2a, or PGE2) rather than blocking their production. Each of these prostanoids has at least 1 receptor. PGE2, the prostanoid most involved in pain and inflammation (but that also has positive effects in the stomach and kidney), has 4 receptors (EP1-4). The EP4 receptor is the receptor that is most important in pain and inflammation.
Galliprant is a selective EP4 antagonist, meaning that it blocks the action of PGE2 at the EP4 receptor, but it does not prevent the production of PGE2 or action of it at the other 3 receptors.
With this novel mechanism of action, the safety profile of Galliprant is different than that of COX-inhibiting NSAIDs. Head-to-head studies have not been performed comparing the safety or efficacy of Galliprant with other NSAIDs. However, the results of studies for the approval of Galliprant suggest that there is a wider margin of safety and efficacy should be equivalent compared to other NSAIDs. Initial clinical experience with Galliprant meets these expectations, but since it has only been on the market for a few years, long term data is not yet available.
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