NSAIDs: Who are they?

You may have heard of NSAIDs, and probably not a few times. But, more than hearing about it, do you know who they are? What is the function? How do they work?

If the answer is “no”, stop everything you are doing now, and read this article, as this is an extremely relevant subject that will accompany you for the rest of your life, believe me.

To begin with, what does NSAIDs mean?

NSAIDs are Nonsteroidal Anti-Inflammatory Agents. Not being steroid means that there are no steroidal hormonal components in the composition of such drugs.

What is the purpose of NSAIDs?

As the name says, one of the important purposes of NSAIDs is the anti-inflammatory effect, but other important effects can also be obtained from the use of such a drug class.

For example, in fever, NSAIDs can be used. Or, even for analgesic effect, they are very much in demand.

How do NSAIDs work?

NSAIDs have an action that promotes central and / or peripheral inhibition of an enzyme called cyclooxygenase, commonly known as COX. From this inhibition, a number of other substances are no longer produced and thus, we have control of some situations such as fever, pain and inflammation.

But before we get into the types of NSAIDs, we need to understand what their mechanism of action is, as this will make it easier to understand some of their peculiarities.

Mechanism of action: The arachidonic acid cascade

Do you know this waterfall? Have you heard? Do you know why it starts?

Arachidonic acid is a normal component of our cell membranes. When any cell injury or stimulus occurs, our cell membrane is also damaged, and then phospholipase A2 is activated, which phosphorylates and releases arachidonic acid. From there, a cascade begins.

Arachidonic acid is a substrate for the production of various substances that will be produced by different routes: the Lipoxygenase (LOX) pathway, and the life of cyclooxygenase (COX) pathway.

The LOX pathway produces leukotrienes, which have functions such as chemotaxis, vasoconstriction, bronchospasm and increased vascular permeability. Generally, the increase in its production is related to inflammatory diseases, such as asthma.

The other pathway that can use arachidonic acid as a substrate is the COX pathway, which is the main pathway to be studied today. When arachidonic acid is converted by COX, it produces prostaglandins and thromboxane.

Which prostaglandins are produced? Different types are produced, such as PGI2 (prostacyclin), PGD2, PGE2, PGF2α, among others. And thromboxane A2 (TXA2) is also produced. But knowing these various names is of no use if we cannot explain the function of these compounds, right !?

PGI2 is a prostacyclin that has some essential functions, such as vasodilation and reduced platelet aggregation (that is, it prevents the formation of thrombi).

Thromboxane A2, on the other hand, is a vasoconstrictor and increases platelet aggregation, therefore having a thrombogenic character.

And PGD2, PGE2, PGF2α promote vasodilation and edema. But PGF2α have an important characteristic, as they act mainly on uterine cells, promoting uterine contraction, acting in the process of menstrual cramps.

And now that we understand what substances are produced and some of their main actions, let’s understand where NSAIDs come into this process.

NSAIDs, as already mentioned, inhibit COX, that is, they inhibit the production of substances produced in the COX pathway, but do you think that COXs are produced only in non-physiological conditions, or do they have physiological actions?

Looking at the characteristics of the substances we talked about above, what do you think? Everything indicates that they participate in physiological processes, don’t they !? And if they are inhibited, what can this generate or change in our organism? Have you ever stopped to think about these issues?

The different types of COXs

We have in our body three main subtypes of the COX enzyme: COX 1, COX 2 and COX 3. The substances to be produced vary according to which COX acts, so the importance of knowing the different types of COX.

COX 1

COX 1 is a constitutive enzyme, that is, it is of paramount importance for physiological and homeostatic processes. By the action of this enzyme, prostaglandins are produced that act on the gastric mucosa, promoting its protection, since they reduce the secretion of HCl, and increase the production of mucus rich in bicarbonate, in order to regulate gastric acidity.

COX 1 also promotes the production of thromboxane A2, which is a pro-aggregating substance. Controlled platelet aggregation is of paramount importance for life, is part of the first stage of the hemostasis process, controlling hemorrhagic processes.

There is also the production of vasodilating prostaglandins that act at the renal level, increasing the glomerular filtration rate (by increasing blood flow in the kidneys) to normal levels.

And you may be thinking at this point: what is the point of inhibiting an enzyme that mediates several processes necessary for homeostasis?

This question makes perfect sense, and we will see next that some NSAIDs do not inhibit this enzyme, in order to maintain their physiological actions.

COX 2

Another type of COX, is COX 2. Unlike COX 1, most COX 2 is induced, that is, it is not constitutively present in our body. It is produced in the face of a stimulus.

The induced COX 2 is mainly related to inflammatory processes. Related to fever, pain and inflammation.

But there is also the constitutive COX 2, which has important functions. The first is that, in the macula densa, there is an important expression of COX 2, and this acts by controlling the glomerular filtration rate and sodium excretion.

Another place that has COX 2 is in the vascular endothelium, and its action leads to the production of PGI2, do you remember what this substance does? Vasodilation and antiplatelet function, that is, antithrombogenic potential.

COX 3

COX 3 (or COX 1b) is mainly expressed in the central nervous system, and is present in processes of fever and pain.

Now that we know where the substances originate, their functions and which COX is involved in the process, we can talk about the types of NSAIDs.

Types of NSAIDs

There are different types of NSAIDs on the market, and the difference between them is: which COX is inhibited.

We have reversible and irreversible NSAIDs.

Irreversible

NSAIDs of the irreversible type are those that irreversibly bind to COXs. I’m sure you’ve heard of AAS, also known as aspirin, or even acetyl salicylic acid. AAS was the first NSAID, and it is the example of an irreversible NSAID.

As I said, the big difference from NSAIDs is that COX is inhibited by it.

AAS is a non-selective NSAID, that is, it blocks both COX 1 and COX 2, but it has a greater affinity to COX 1.

And why use AAS? Low dose ASA blocks mainly COX 1 present in platelets and in the vascular endothelium. Remember that I said earlier that COX 1 is an important producer of thromboxane A2?

AAS, by inhibiting COX 1, promotes a reduction of thromboxane A2, and thus reduces its thrombogenic effect.

At the same time, the COX 2 present in the endothelium is almost not inhibited, the production of PGI2, which is an important anti-aggregating substance, remains and thus promotes one of the most well-known functions of AAS, which is the anti-aggregating effect.

But as AAS is a COX inhibitor, it can perform other functions, such as the antipyretic effect, as it blocks COX 2, reduces the production of PGE2. And how does it interfere with fever?

When an infection occurs, microorganisms release pyrogens. These exogenous pyrogens are recognized by the defense cells, leukocytes, which produce and release endogenous pyrogens, such as PGE2. We have, in the pre-optic area of ​​the hypothalamus, a set point , which regulates our body temperature at 37 ° C. PGE2 promotes a change in the set point , increasing the value by 37 ° C. That is, the hypothalamus does not perceive that the temperature is high, and, thus, there is no temperature control, and thus we have a feverish condition.

When NSAIDs inhibit COXs, they also inhibit this production of PGE2, and, with this, the set point returns to normal, and the organism that is at an elevated temperature initiates some mechanisms for heat loss, such as sweating.

AAS is also a pain reliever. Prostaglandins reduce the pain threshold. This means that it becomes easier for a stimulus to trigger pain, because the threshold to be reached is lower. As AAS inhibits prostaglandin production, it prevents this change in the threshold from happening.

Reversible

Unlike irreversible NSAIDs, reversible NSAIDs temporarily inhibit COXs.

Among the reversible NSAIDs, we have some different subclassifications: COX non-selective reversible NSAIDs; the partially selective NSAIDs for COX 2; Highly selective NSAIDs for COX 2; Selective NSAIDs for COX 3.

COX non-selective reversible NSAIDs

These NSAIDs act by reversibly inhibiting both COX 1 and COX 2. We have some specimens that I am also sure you have heard of and have probably used.

The famous dipyrone, ibuprofen and diclofenac are non-selective NSAIDs. I said you knew it and had already used it, right? !!!

These NSAIDs are widely used, as they have antipyretic effects (control feverish conditions) and analgesic (control pain conditions of mild intensity).

These effects occur through the same mechanisms that I mentioned earlier about AAS, and the simple explanation for this is that they inhibit COXs (COX 1 and COX 2).

Ibuprofen (isobutylpropanoicophenolic acid) is a non-selective, non-steroidal anti-inflammatory, widely used, being an important option in many pathologies.

It is listed by WHO (World Health Organization) and PAHO (Pan American Health Organization) as an essential medicine. It inhibits both COX 1 and COX 2.

It is a drug indicated in several situations that include inflammation, pain and fever, such as headache, migraine, primary dysmenorrhea, rheumatoid arthritis and osteoarthritis.

Partially selective NSAIDs for COX 2

COX 2, as you already know, for the most part, is induced, being released in inflammatory processes, for example. While COX 1, in turn, is basically involved in constitutive and homeostatic processes.

Thus, having an NSAID that mainly inhibits COX 2 can be interesting in some cases.

Partially selective NSAIDs for COX 2 are drugs that have a greater affinity for COX 2, but they can also inhibit COX 1. Who are they? Nimesulide, meloxicam and etodolac are examples of this category.

Nimesulide is widely used to treat pain, fever and inflammation. Indicated in acute pain, osteoarthritis and primary dysmenorrhea.

However, despite being widely used, it presents important risks already reported in several countries, such as the risk of liver damage related to prolonged use and old age, and which, although there are no reports in Brazil, represents a major concern.

Highly selective NSAIDs for COX 2

Highly selective NSAIDs for COX 2 are those that selectively inhibit COX 2, that is, they do not inhibit COX 1. Thus, the gastric protective function of prostaglandins produced via COX 1 is not affected. And it inhibits COX 2, controlling inflammation, fever and pain.

But, at the beginning, we said that in the vascular endothelium there is COX 2, and this is important for the production of prostacyclin (PGI2), a vasodilating and anti-aggregating substance. If there is inhibition of COX 2, there is no production of PGI2, and this can be harmful, agree !? For this reason, individuals who are at risk or have a history of thromboembolic events cannot use this class of NSAIDs.

The group’s representatives are coxibs, the most used being celecoxib, an NSAID used in the treatment of osteoarthritis, rheumatoid arthritis and as an analgesic, being indicated mainly in patients with gastric ulcers and who are not at risk for thromboembolic events.

Selective NSAIDs for COX 3

The selective NSAIDs for COX 3 (COX 1b), are represented by dipyrone and paracetamol. COX 3 is related to pain and fever processes and, therefore, its inhibition promotes antipyretic and analgesic effects.

Dipyrone has a small effect of reducing inflammation, remembering that it is a non-selective inhibitor and can inhibit COX 2. However, it is not used for this purpose, as there are other drugs on the market that have an anti-inflammatory effect. more potent.

Both dipyrone and paracetamol do not act directly on inhibition. This occurs through the active metabolites of drugs. Both drugs are widely used, and often incorrectly by self-medication. Who has never resorted to dipyrone in pain or fever? !!

The main problem is the use of incorrect doses, especially doses higher than recommended. With that, toxic effects can happen.

Conclusion

We saw, therefore, that NSAIDs are very important to control certain situations, and I believe that you realized how much they are present in our daily lives.

Knowing the different types of NSAIDs and their role, according to the inhibited enzyme, is a big step in understanding the pharmacology of NSAIDs.

 

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