What are NSAIDs?

Non-steroidal anti-inflammatory drugs, or NSAIDs, are a class of drug that is commonly used (worldwide) to reduce inflammation and pain. As we will see in the next blog by Dr Nick Tiller, NSAIDs are also used in sport for performance reasons. To understand what NSAIDs are and how they work, we need to have a basic understanding of the inflammatory response. This blog outlines what NSAIDs are, how they work, and provides the basis of their use in sport.

Prostaglandin formation

Before we explore the potential effects of NSAIDs, we must first consider the mechanisms behind pain sensations. Following tissue injury or irritation, an enzyme called phospholipase A2 is released. This enzyme will convert phospholipids in the cell membrane into arachidonic acid. Arachidonic acid serves as a substrate for cyclooxygenase (COX) to form prostaglandins and these prostaglandins have various effects on different organ systems.

COX enzymes

The COX enzyme exists in different forms: COX-1 and COX-2. Below is an outline of each form:

• COX-1: This isoform is expressed constantly throughout the body and is responsible for producing thromboxane and prostaglandins that stimulate normal body functions. They are, amongst other functions, responsible for the secretion of protective gastric mucus, the regulation of gastric acid, the promotion of platelet aggregation (important for blood clotting), and the maintenance of renal blood flow.

• COX-2: This isoform is not constantly expressed in most tissues. It is induced locally at the site of damage or irritation. COX-2-helps the production of prostaglandins that mediate inflammation, pain, and fever.

In summary, these COX enzymes play an important role in inflammation and pain, but also in a whole host of other physiological functions.

How do NSAIDs work?

NSAIDs primarily act by inhibiting COX enzymes, leading to decreased production of prostaglandins. Effects are both central and peripheral, as shown in the graphic above. The decreased production of prostaglandins results in anti-inflammatory and pain reducing/analgesic effects. There are different categories of NSAIDs, some will specifically act on COX-1, some will only work on COX-2 and some are non-specific (will act on both). A common NSAID is ibuprofen which is non-specific (affects all COX enzymes). Whereas aspirin affects specifically COX-1.

Adverse effects of NSAIDs

As one would expect, if COX enzymes are blocked, it is not just inflammation and pain that are affected but all other normal function would be inhibited too. Inhibition of all these other effects can have negative consequences. In recent years these consequences have become better understood, and there is an increasing number of studies on toxicity. Due to this understanding, healthcare practitioners are now much more careful with prescribing NSAIDs. Below we will discuss some of the reported negative effects.

Gastrointestinal effects

The most common adverse effects of NSAIDs are observed in the gastrointestinal tract. Normally COX-1 increases the synthesis of prostaglandin E2 (PGE2) as well as prostacyclin (PGI2). Both play important roles in the production of protective mucus and regulating of blood flow to the gut. It has been reported that inhibition of COX-1 increases the risk of gastrointestinal bleeding and peptic ulcers, particularly with agents that are more selective for COX-1 and especially when used in high doses.

Antiplatelet effects

Inhibition of COX-1 also affects thromboxane A2 (TXA2) production, which promotes platelet aggregation and has implications for blood clotting. A decrease in TXA2 formation results in an antiplatelet effect which in turn increases the risk of bleeding. Aspirin is particularly known for this effect as it irreversibly inhibits COX-1 in platelets, leading to prolonged antiplatelet effects even after the medication is stopped.

Renal effects

NSAIDs can also impact kidney function. Renal prostaglandins play and important role in maintaining glomerular filtration rate (GFR). In compromised kidney function, such as in heart failure or old age, the production of prostaglandins becomes a key factor for preserving renal blood flow. Especially in these patients, NSAIDs may increase the risk of kidney injury by suppressing renal prostaglandin production.

Cardiovascular effects

While agents like aspirin can have protective cardiovascular effects due to their antiplatelet properties, drugs with high COX-2 selectivity may increase the risk of cardiovascular events. This occurs because selective inhibition of COX-2 can tip the balance in favour of TXA2 formation, leading to increased vasoconstriction and platelet aggregation, which raises the risk of myocardial infarction and stroke.

Summary

In summary, understanding the pharmacology of NSAIDs is crucial for their effective use in managing inflammation and pain. While NSAIDs provide significant therapeutic benefits, they also carry risks that must be carefully considered, particularly regarding gastrointestinal, antiplatelet, renal, and cardiovascular health. In the next blog we discuss whether NSAIDs should be used to aid performance in a sports setting.