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Biomedical Research

COX Fight: A Closer Look at NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of some of the most widely prescribed analgesics in the world. This article takes a look at NSAIDs’ mechanism of action and how this is linked to their side effects.

By Adaora Belonwu

Published 8:24 PM EST, Tues March 9, 2021

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of some of the most widely prescribed analgesics in the world. Their use dates back to earlier than the 19th century, which was a period that marked a time when the European beaver was headed towards extinction after being extensively hunted for its castoreum. Castoreum, among other things, is a salicylic-rich secretion of the beaver anal gland sought after for its analgesic and anti-inflammatory properties. It would take nearly a century later for scientists to link castoreum’s benefits to the spiraea (plants like willow) in the beaver’s diets and even longer to isolate the salicin compound from willow bark and substitute one of the hydroxyl functional groups with an acetyl group. Thus, in 1899, acetylated spiraea (aspirin)  was synthesized for the first time, and the face of pain-medicine was changed forever.

[Figure 1: acetylation of salicylic acid]

However, despite being considered as some of the world’s safest drugs, the use of NSAIDs is not infallibly positive as their mechanism of action increases the risk of issues such as gastrointestinal and cardiovascular complications by up to 20% in prolonged use compared with non-NSAID users. Furthermore, links between increased risk of myocardial infarction and NSAIDs have been observed in several studies spanning the past several decades. All this can be attributed to the molecular targets and mechanism of NSAIDs.

ALL NSAIDS ARE CYCLOOXYGENASE INHIBITORS

[FIGURE 2: Arachidonic acid cascade]

Cyclooxygenase is the molecular target of NSAIDs that work primarily through inhibition, thus decreasing prostaglandin production. This gives them their antipyretic, anti-inflammatory, and analgesic effects. To understand how the effects of NSAIDs come to fruition, it is first necessary to look at the inflammatory response. Following tissue damage, phospholipase is released at the site of injury. This enzyme converts the phospholipids within the cell membrane into arachidonic acid, which is the substrate of cyclooxygenase isoenzymes. Isoenzymes (or isozymes) are enzymes that differ in their amino acid composition and sequence but catalyse the same reaction due to their similar conserved structure. However, they usually have different physiological roles and intracellular locations. There are two isoenzymes of cyclooxygenase (COx). COx-1 is constitutive (expressed constantly throughout the body), acting as a source of thromboxane, and prostaglandins which stimulate regular bodily functions. COx-2 is inducible at sites of inflammation, meaning that COx-2 derived prostaglandins mainly regulate inflammation, pain, and fever.  NSAIDs can be divided into three categories based on their selectivity for COx isoforms, and it is this disparity in selectivity which contributes to the side effects of NSAID use. 

COX-1 Selective 

Complications with the gastrointestinal tract are the most commonly reported side effect of prolonged NSAID use. Here, COx-1 mediated production of prostanoids PGE₂ and prostacyclin play important roles in the synthesis of gastric mucus, which not only serves to protect the stomach lining from being damaged by its own stomach acid but also maintains general gastrointestinal blood flow. Therefore, the selective inhibition of COx-1 by drugs such as ketoprofen, naproxen, and aspirin has a knock-on effect that, in prolonged use, can cause gastrointestinal bleeding and ulcers. The highest risk NSAIDs are most likely to belong to this category. Another negative side effect is associated with the inhibition of thromboxane A₂ (TXA₂). As this chemical promotes platelet aggregation, a decrease results in an increased risk of prolonged bleeding. This side effect is most prevalent in aspirin, which is unique in its ability to inhibit COx-1 in platelets permanently. However, this effect can be leveraged in low doses, as seen in the treatment of some hypertensive patients. 

COX-2 Selective and Side Effects

While NSAIDs such as aspirin can have a cardiovascular effect due to their antiplatelet aggregation properties, NSAIDs with high COx-2 selectivity, take etodolac or celecoxib, for example, can have the opposite effect. Under regular conditions, there is a balance between prostacyclin and TXA₂. The production of prostacyclin is mainly performed by COx-2 in the endothelium, making it responsible for vasodilation and inhibition of platelet activation.  Conversely, TXA₂ is mainly produced by COx-1 in platelets and, as aforementioned, responsible for vasoconstriction and platelet aggregation. The introduction of selective inhibition of COx-2 offsets this balance in favour of TXA₂ promoting vasoconstriction and platelet aggregation and thus is the primary reason behind the increased risk of myocardial infarction and stroke amongst NSAID users.

Non Selective and Side Effects

Renal prostanoids, specifically PGE₂ and PGI₂, cause dilation of the renal afferent arteriole, which is important for maintaining glomerular filtration rates. Under regular conditions, these prostanoids have a negligible effect on renal perfusion but can become a significant hindrance when renal function is weakened (for example, in old age or kidney failure). For this reason, some NSAIDs are contraindicated in susceptible patients due to their ability to exacerbate the risk of renal injury by potentially compromising renal blood flow.

Conclusion

Nonsteroidal anti-inflammatory drugs remain to this day one of the safest and most highly prescribed drugs. They work through the inhibition of cyclooxygenase, which is required to convert arachidonic acid into prostaglandins and prostanoids, including thromboxanes and prostacyclins. NSAIDs’ therapeutic effects can be attributed to the reduction of these chemicals mainly during the inhibition of inducible cyclooxygenase isoforms. In a similar fashion, their side effects and risks stem from them tampering with the body’s delicate balance of aforementioned prostanoids during key bodily processes such as mucus production in the gastric lining, platelet aggregation, and renal perfusion in vulnerable patients. 

Adaora Belonwu, Youth Medical Journal 2021

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By Adaora Belonwu

Adaora Belonwu is a student at St Michael's Catholic Grammar School in London. Currently she is interested in the fields of embryology, immunology and regenerative medicine.

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