8⃣ AINES (ANTI-INFLAMATÓRIOS NÃO ESTEROIDES) | Anestesia é o Básico #8

Do you know this lady? She's Ms. Maria, my mom.

She will be in today's video lesson. Bring it on! Non-steroidal anti-inflammatory drugs What's up NAVE crew!

In today's Anaesthesia Unravelled video lesson we will be talking about non-steroidal anti-inflammatory drugs. The NSAIDs are certainly the most commonly used painkillers in the world, both in medicine and veterinary. Even before I could contemplate the idea of becoming a vet, there was a painkiller that I knew worked for absolutely anything, the "Bufferin" (Aspirin).

That was because, regardless of the problem, Ms. Maria would give Bufferin to everyone. Bufferin will fix it.

Go on! Take Bufferin, it works for anything! Bufferin will do it!

For this one you'll need to take Buferin and rifamycin. Mom, you're overdoing it. Well, I don’t know.

We can’t really argue with mother’s wisdom, right? The excessive use of NSAIDs are generally related to 5 reasons: the first is that all painful process has some inflammation involved. The second is that the NSAIDs are excellent pain relievers for mild to moderate pain.

The third is that they are relatively safe when compared to other analgesic groups. The fourth is that the oral route promotes excellent bioavailability, and the fifth is the ease of purchase, because you don't need a prescription to buy an NSAID. Before we discuss NSAIDs, we have to understand the inflammatory process itself.

Inflammatory process The inflammatory response is a natural process of the body that has two main purposes. The first is to serve as a barrier against pathogens in the case of an injury and the second is to prepare that region for tissue repair. The inflammatory process is extremely complex to understand, and we won't be able to cover it all here in this video lesson.

I'm sure there's a lot of great material out there to help you understand exactly how it works, but in short, we can see in this picture that, following tissue injury, defense cells migrate to protect the body from damage. Platelets have the function of containing local bleeding; the mast cells, of releasing stamina to promote vessel dilation and, thus, facilitate cell recruitment; neutrophils and macrophages have the function of promoting phagocytosis as the first protective barrier; the macrophages will also secrete cytokines, that will activate the immune system to accelerate tissue healing. So, this whole process that releases bradykinin, serotonin and histamine and eicosanoids, that are the prostaglandins, prostacyclin and thromboxanes, have the function of repairing that entire part.

All of that promotes that five cardinal signs of inflammation, like in the picture, and what we have is heat, redness, swelling, pain and, depending on the situation, loss of function. The inflammatory response has a lot to do with the immune system, which I can't really give an in depth explanation, so we will focus on the physiopharmacological part. To understand the mechanism of action of NSAIDs, we need to remember the arachidonic acid cascade.

This cascade starts at a cell injury, when the phospholipid structure is affected and the phospholipase A2 transforms these phospholipids into arachidonic acid. The arachidonic acid, in turn, follows two pathways: the lipoxygenase pathway, that forms leukotrienes, and the cyclooxygenase pathway, that originates prostaglandins, prostacyclins and thromboxane. The main functions of the eicosanoids, as they are called, is to promote vasodilation, pain, chemotaxis and platelet aggregation.

So, let's go back to the picture and pay attention to two enzymes. The first is phospholipase A2. This enzyme is blocked by corticosteroids, that are also anti-inflammatory drugs, but steroids.

We don't use corticosteroids in the postoperative period because they strongly inhibit tissue repair and also the immune response after infections. So, for us to treat inflammation we're going to block the cyclooxygenase pathway. COX-1 / COX-2 ratio There are two cycloxygenase enzymes: COX-1, which is theoretically known as constitutive COX, and takes part on an organism's homeostasis.

It is closely related to the renal and hepatic vessel dilation processes and also gastrointestinal protection. On the other side, we have the COX-2, which is considered inducible. So, it's produced in greats amounts in cases of inflammation, in which it's related to the vasodilation that occurs in inflammation and also pain, increasing the excitability of the dorsal spinal cord.

There is evidence of the existence of a COX-3, which is a variant of COX-1 and was found only in the central nervous system. For a long time, these COXs were labeled as COX-1: constitutive and COX-2: inducible, but today we know that they don't work that way, they have a certain interaction, COX-2 also participates in physiological protection. Why is it important to know the difference between COX-1 and COX-2?

Because, although COX-2 participates in physiological protection, it is much better for us if the medication blocks COX-2 than COX-1. Today, we basically work with three categories of anti-inflammatory drugs: the non-selective, that block COX-1 and 2 equally, the preferential, that have a tendency to block more COX-2 than COX-1, and the selectives, that block a much larger quantity of COX-2 than COX-1. So, today, what we have is the demand for NSAIDs that are COX-2 preferential blockers or even COX-2 selective.

So your point is that the COX-2 selective NSAID is better? Well, that's a very important point: the anti-inflammatory and analgesic effects are basically the same, they don't differ all that much. Obviously, some anti-inflammatories are going to be better in one species than the other, but, overall, they share the same effect.

The major problems are the adverse effects. I get it, the selective NSAIDs have no adverse effects. No, that's not what I mean.

Adverse effects Every NSAID can potentially cause some problem. Obviously, the preferential and selective ones tend to cause less problems, that is, adverse effects, than non-selective ones, but there are several factors that influence this. The first is the dosage.

Obviously, the non-selectives have a narrower safety margin compared to the selectives. Another factor is the physiological condition of the patient, we will see that, depending on the physiological condition, even a selective NSAID can cause problems, and we also have individual variation, sometimes we use a very low dose and the animal shows adverse effects anyway. So it is very important that we know the adverse effects, so that we may suspend the treatment if need be.

The most common adverse effects are related to the gastrointestinal system. NSAIDs can promote microlesions and micro necrosis in the stomach wall by decreasing blood flow and also the protective layer. There's also local irritation when the administration is done orally.

In this case we see diarrhea, colitis, melena, hematemesis, all that is secondary to injury to the gastrointestinal system that can go from minor to aggressive. These lesions are usually associated to the non-selective NSAIDs, such as flunixin meglumine, ketoprofen and phenylbutazone in equines. But I’ve seen meloxicam, which is a COX-2 preferential NSAID, promote the same effect.

Kidney injuries are also related to the use of NSAIDs. We have to be cautious, especially in surgeries. The COX-2 has an important role in renal homeostasis, especially in hypovolemic and hypotensive patients.

It is recommended to avoid the use of NSAIDs in patients during hypotension, regardless of whether they are specific or non-specific. That's why it is so important to monitor blood pressure. Then we'll start that discussion of whether or not to use NSAIDs before the surgery.

This is very questionable, as the surgical act itself is already a tissue injury but if you suspect that this animal may end up having hypovolemia during the procedure, it is better to wait until the end. Coagulation can also be altered by anti-inflammatory drugs, since the thromboxane, that comes from the arachidonic acid cascade, is important in platelet aggregation. Other processes that people used to say that were affected by the use of NSAIDs, such as wound healing, cartilage repair and bone repair, new studies demonstrate it's not so.

The use of NSAIDs, preferably COX-2 selectives, even tend to improve healing, and we shoudn't forget about their importance in the postoperative of orthopedic surgeries, it is part of the analgesic therapy in these cases. A frequently asked question is in the occasion of NSAID adverse effects, like if the owner is administering a non-selective NSAID and it results in adverse effects, if it can be immediately exchanged for a preferential or even a selective. The answer is "no".

What we have to do is leave this animal without NSAIDs during a period that we end up calling "washout". This period is 3 to 5 times the half-life of the drug. We obviously need to know the half-life of each medication and then calculate 3 to 5 times that period, and only after that we can exchange the anti-inflammatory for a better one, as a selective or preferential.

Main NSAIDs As I mentioned before, NSAIDs are excellent choices, especially for starting analgesic treatment for acute pain or even chronic pain. Obviously that, depending on the intensity, it should be part of a multimodal therapy. There are dozens NSAIDs used in veterinary medicine, we will address the main groups and divide them into non-specific, preferential and COX-2 selective.

Regarding the non-specifics, we will highlight the flunixin meglumine, phenylbutazone and ketoprofen. These three anti-inflammatory drugs are still widely used in large animals. Some time ago, flunixin meglumine and ketoprophen were used in small animals as well, but today it's not usual.

They're still used in large animals because of the price, as they are very cheap, and unfortunately because of the resistance of veterinarians who work with large animals in using better anti-inflammatories. The flunixin meglumine may be the most popular NSAID in horses, especially in cases of colic. The flunixin has also an interesting effect in ruminants, mainly those that undewent ruminotomy, castration and dehorning.

According to the literature, there's an anti-toxemic dose, that is 5x lower than the clinical dose. It is still used frequently, but there are several recent works that refute this antitoxemic action of flunixin meglumine. We can see in this research in which the authors compared the effectiveness of the flunixin meglumine and the firocoxib in horses that underwent a colic surgery because of an intestinal torsion, and they found that firocoxib was much better at promoting the recovery of the intestinal mucosa compared to the flunixin meglumine.

The phenylbutazone is widely used in musculoskeletal pain. The problem with phenylbutazone is that it's action is shorter compared to flunixin meglumine, and it also has a greater potential to promote gastrointestinal and kidney injuries, also compared to flunixin meglumine. Ketoprofen is also used frequently in large animals in musculoskeletal conditions.

Out of the three, perhaps it is the one that promotes the most important alteration in blood clotting, besides the gastrointestinal ones. That's why it stop being used in small animals. I honestly don't even remember how the bottle of these three medications is, I haven't used them for a long time, but it is still used in large animals, people do whatever they want, right?

I wouldn't do it on my own animal. . .

Adriano, teach us something about diclofenac! NO. In the table we can see the doses and routes of flunixin meglumine, phenylbutazone and ketoprofen in horses and ruminants.

Regarding the preferential blockers, the two most popular are meloxicam and carprofen. Carprofen is more prefential of COX-2 than meloxicam is, except in horses, where the opposite occurs. Despite being one or the other, these drugs are already quite interesting.

In addition to being excellent choices for the treatment of acute pain, they can be used for long periods, mainly in small animals, and the adverse effects are discreet and rare. We can see in this very interesting study that the authors used several NSAIDs in dogs for 90 days, in which meloxicam and carprofen ended up being excellent choices, promoting very few adverse effects. These two drugs are also interesting in large animals.

There are several studies demonstrating that they have excellent analgesic effect, both in horses with colic or laminite, and also in ruminants after rumenotomy, castration or dehorning. Here we can see the doses and routes of meloxicam and carprofen in small and large animals. The COX-2 selective anti-inflammatory drugs are known as coxibs.

The first veterinary coxib was deracoxib, that in small animals, blocked 30x more the COX-2 than COX-1. Then there was firocoxib, which is 10x more selective for COX-2 than deracoxib. The most popular coxibs today in veterinary are firocoxib, robenacoxib and mavacoxib.

All similar, they block a lot more COX-2 than COX-1, so their adverse effects are less frequent than other NSAIDs. In terms of analgesic effects, they are very similar. The big difference between them is that each is a patent from a giant pharmaceutical company.

But they also a few other differences. All these three NSAIDs can be used in dogs, but in cats, only the robenacoxib is allowed. For horses, we only have the established dose of firocoxib.

The firocoxib has been extensively tested in dogs and there's a very interesting work in which they used firocoxib for a year and only a few animals showed any gastrointestinal effect, and when they did, very mild, demonstrating that it is quite safe in analgesic therapy for chronic pain in dogs. The same is true for horses, it has been widely used in foals and horses for long periods without promoting any gastrointestinal or renal problems. The only thing we need to be careful about firocoxib is that it has some degree of embryotoxicity, so it is not indicated in pregnant animals.

The robenacoxib has been used in dogs and cats for more than six months and also had no adverse effects. The mavacoxib is the most different one out of the three, a single dose in the dog lasts up to 14 days, and from the second dose, 27 and 40 days. It seems great, right?

Because then we give the analgesic therapy once a month, theoretically, but I have serious reservations about it. If that animal shows any kidney problems during that period, there's nothing we can do. We'll need to use a support treatment to handle the problem.

This table shows us the doses and routes of the main coxibs used in veterinary medicine. For acute pain, I prefer to use meloxicam and for chronic pain, meloxicam, carprofen or firocoxib. Dipyrone (metamizole) and paracetamol (acetaminophen) There two NSAIDs have little anti-inflammatory effect they have a more prominent analgesic and antipyretic effect.

In fact, what studies show is that they work better as analgesic adjuvants, and that they block mainly that COX-3 that we mentioned before, located in the central nervous system, and not in the periphery. Here in Brazil, it's more common to use dipyrone, but in North America people prefer to use paracetamol. What's not right is to stop using the other NSAIDs because we are using dipyrone or paracetamol.

We just have to remember two things: paracetamol is biotransformed by glucuronidation, so it cannot be used on cats under any circumstances, dipyrone, on the other hand, has a greater anticoagulation effect than other NSAIDs, so we have to be careful in patients with clotting disorders. As a conclusion of this video lesson, we have to remember that practically all painful processes come with inflammation. We should not use corticosteroids in postoperative analgesic therapy, especially for chronic pain.

The best anti-inflammatories are those that block COX-2 preferentially or even selectively, but we must not forget that every NSAID can potentially cause injuries, mainly due to the dose. and finally, in situations involving excruciating or chronic pain, the anti-inflammatory must be part of a multimodal therapy and not be the only option. If you persisted to this point, you must have liked this video lesson, right?

Then take advantage of it and leave us a comment, suggestions or praises, that's very important for us. And also follow us on social media, because we are frequently discussing the subject and the articles from the video lessons. See you soon!