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It's Medicosis Perfectionalis, guys, where medicine makes perfect sense. Today is the 19th video in my series about bleeding and coagulation. Today, let's talk about the cyclooxygenases.
I've talked about the arachidonic acid pathway before, which was an awesome video that you must watch. Today, let's talk about the cyclooxygenases and the difference between cyclooxygenase one and cyclooxygenase, guess what, two. So let's get started. [Music]
Quick review of my video on the arachidonic acid pathway: We have the cell membrane, also known as the plasma membrane, also known as the lipid bilayer. It has the lipid bilayer, and then our proteins and carbohydrates within it. Phospholipids—those are the type of lipids—phospholipid, cholesterol, and other lipids. Cholesterol lipids in your nerve cells. Phospholipids will form the arachidonic acid pathway. There is an enzyme here responsible for the steps; we will call it phospholipase. So, phospholipase A2—every enzyme, most enzymes have an "ase"—it will convert phospholipid into the arachidonic acid, or to be more precise, it will free the arachidonic acid from the phospholipid. As you know, the phospholipid of your cell membrane has heads and tails and the stupid stuff that you learn in physiology. Okay, why do you have a bilayer? Because there is water outside, water inside, and lipid in between. So you need to have the amphipathic, like an amphibian kind of mechanism.
The arachidonic acid, polyunsaturated, whatever—it's not an essential fatty acid, or in other words, it's conditionally essential. Which means, under normal circumstances, it's not essential. However, when you are deficient in linoleic acid, which is the parent of this arachidonic acid, now the arachidonic acid becomes essential, which means you have to eat it in your diet; otherwise, you'll be deficient in the arachidonic acid pathway, which is not fun. Chemically, it's a 20-carbon carboxylic acid. Phospholipid portion of the—okay, inflammatory mediator, which will cause vasodilation, yeah, increase vessel permeability and vasodilation to promote inflammation. It's freed from the phospholipid by the great phospholipase A2, and this is inhibited by steroids. Twice. Steroids are anti-inflammatory. If arachidonic acid is inflammatory and there is a drug that prevents its formation, then, by definition, steroids are anti-inflammatory. No kidding. By using the Aristotelian method: two premises and a conclusion. One: if arachidonic acid is pro-inflammatory. Two: steroids prevent arachidonic acid formation. Then three: steroids are anti-inflammatory.
So here is the sequence: membrane, phospholipid into arachidonic acid. What's the enzyme? Phospholipase A2, inhibited by steroids. But if it's not inhibited, it's going to produce the arachidonic acid pathway, and it has two different pathways: the prostaglandin pathway and the leukotriene pathway. For it to become prostaglandin, it needs an enzyme called cyclooxygenase. For it to become leukotriene, it needs an enzyme called lipoxygenase, to be specific, 5-lipoxygenase. I don't know; it doesn't matter to me. We have two types of cyclooxygenase: we have the cyclooxygenase one, and because doctors are very creative, they name the other one cyclooxygenase two. Like when we have two types of diabetes, we choose the most creative method of nomenclature: type one diabetes and guess what, type two diabetes. When you have three categories of personality disorders, let's name them Class A, Class B, and Class C. Very creative. These doctors are just genius.
In case you didn't hear, I have 50 hematology cases on my Patreon account. Go to patreon.com/medicosis. Warning: these are difficult. Let the phospholipid speak about himself: I set the arachidonic acid free from the tyranny of phospholipids. I let arachidonic acid loose to promote my agenda of inflammation. However, steroids can send me to the cleaners. Arachidonic acid pathway: prostaglandin, leukotriene. Prostaglandin, depending on the—if you are the platelets, let's form thromboxane A2, procoagulation. If you are the endothelium, let's form prostacyclin, to keep the blood cycling, which is anti-coagulation. Both of them have the same route, and I've told you why before. What does thromboxane do? It vasoconstricts, increases PL aggregation. What does prostacyclin do? Keeps the blood cycling by vasodilation and preventing PL aggregation. You have different types of prostaglandin. We start with prostaglandin I2, PGH2, we have PGE2 and PGD2, and then we have the thromboxane and PGI2, which is the prostacyclin.
If you want to add some pharmacology to the picture: steroids inhibit the phospholipase A2. All of the stuff promotes the phospholipase A2 or stimulates it. Aspirin, non-steroidals, inhibit the cyclooxygenase, and we have the zileuton inhibiting the lipoxygenase. The montelukast and the other leukotrienes, they are leukotriene receptor inhibitors. Both of these classes of drugs are good for asthmatics. Leukotrienes are horrible for asthmatics. Now we know why we use inhaled steroids for asthmatics; we use leukotriene inhibitors again for asthmatics. Aspirin is antiplatelet because it inhibits thromboxane A2. Steroids are the most powerful anti-inflammatory drug ever because they inhibit both pathways. Aspirin can worsen asthma symptoms because if you have two pathways and you have the cyclooxygenase here and you have the lipoxygenase and and leukotriene here, if you inhibit this pathway, all of the leukotriene is going to be converted into leukotriene, which makes the life of asthma patients hell.
What's really new in this video is there are two types of cyclooxygenase: cyclooxygenase one and guess what, cyclooxygenase two. Both cyclooxygenase one and cyclooxygenase two produce prostaglandins that promote pain, fever, and inflammation. What's different? What's unique about cyclooxygenase one? Two things actually. First, it produces thromboxane A2. Cyclooxygenase two will never produce thromboxane A2. Never, ever, ever. However, cyclooxygenase one will. So cyclooxygenase one will promote coagulation by activating the platelets and promoting their aggregation. Cyclooxygenase one also produces prostaglandins that protect the stomach inner lining from the acids. If you want to promote coagulation, cyclooxygenase one is your guy. If you want to protect the stomach from acids, cyclooxygenase one is your man. So here is a nice mnemonic for you: here is one to remember: cyclooxygenase one, and here is platelets because it's procoagulation, and here's the stomach because it protects the stomach lining. So let's play this game: ask yourself, is it cyclooxygenase one or cyclooxygenase two? How about here? One and two. How about here? One and two. How about here? One and two. How about the platelet, guys? It's only one. How about the stomach lining protection? It's only one.
There are two types of non-steroidal anti-inflammatory drugs, also known as NSAIDs. We have the classical and the new generation. What's the classical? The non-selective cyclooxygenase inhibitors, such as aspirin, ibuprofen, ketoprofen, oxaprozin, etc. They inhibit both COX-1 and COX-2. However, the new generation, it's selective; it's specific; it inhibits only cyclooxygenase two inhibitors. So they, they inhibit only cyclooxygenase two, such as the famous celecoxib. Cool. Here, cyclooxygenase one is free, free to do what? To promote coagulation and to protect the stomach lining. How about, um, selective cyclooxygenase one inhibitors? Now you are becoming an enthusiastic ignoramus, also known as a salesman. There is nothing unique about cyclooxygenase two. There is something unique about cyclooxygenase one; that's why we have selective COX-2 inhibitors to leave one free, because one is unique. There is nothing unique about two, at least as far as I know. I know there is some research that supposedly proclaims that cyclooxygenase one is, um, is like beneficially to be inhibited, and we can in the future make drugs about it. I don't care right now, but let's talk about the side effects of the classical non-selective inhibitors, such as ibuprofen. It increases risk of peptic ulcers, yes, because it inhibits one, and one protects the stomach. It increases the risk of bleeding, yes, because it inhibits one, and one promotes coagulation. Wonderful. About the other selective cyclooxygenase two inhibitors, such as the famous celecoxib: it decreases risk of peptic ulcer, why? Because now one is free. So now, for the first time in history, we have a potent anti-inflammatory drug that is soft on your stomach. Amazing. However, if you are not increasing the risk of bleeding, you are increasing the risk of clotting. There is no way around it. So we have myocardial infarction, increased risk of strokes, etc., etc., etc. Why is that? Because you have left cyclooxygenase one free; you have increased the amount of thromboxane A2 while decreasing the amount of prostaglandin I2, prostacyclin, which keeps the blood cycling. Welcome to coagulation land.
Let's stop talking like professors and start talking like doctors. You have a patient with arthritis and a history of peptic ulcer. Here or she wants an NSAID for his pain symptoms, but he has a peptic ulcer. Use the selective cyclooxygenase two inhibitors. Post-surgery patient: you like to manage the pain; it's a major surgery; let's manage the pain. How about we use a non-selective, something like aspirin? Never do this. Why not? Because aspirin will inhibit the thromboxane A2 when we have just, like, closed your abdomen after a major abdominal surgery. Okay, we need you to clot; we need you to stop the bleeding. We have just cauterized the arteries, closed all of the vessels; we don't want you to bleed, so please coagulate to close all of these opened vessels. Now aspirin will inhibit cyclooxygenase one and two; thromboxane A2 is history, and you will bleed to death after your operation, which is never fun. So cyclooxygenase two inhibitors are preferable after surgery. There are, there are exceptions, of course. Patient with Glanzmann thrombasthenia and arthritis: they want an NSAID for their pain; they have thrombo-platelet asthenia, weak; they have weak platelets. So use the selective inhibitors to leave the cyclooxygenase one free. One is procoagulation because if you use a non-selective like aspirin, the patient already has weak platelets, and now he doesn't have thromboxane A2; he will never coagulate, and he will bleed to death because you are foolish.
There's a famous story about a drug called rofecoxib. Again, see the cyclooxygenase, cyclooxygenase here, and B is the second letter, so it's a cyclooxygenase two inhibitor; that's how I remember it. It's just a mnemonic. So they produced this drug, and it was nice and rosy: we have an anti-inflammatory which is strong, yet soft on your stomach and doesn't cause ulcers, and until they discover that it increases the risk of what? Of clotting. And now, because you watch Medicosis, you know why they removed the drug and took it off market, and what a story. So if you have, like, um, a cousin or something who works with Merck, just say the word rofecoxib or the trade name Vioxx, and they will start screaming and running naked in the street. Sorry, it's written like this, and I'm joking, of course. So dear Merck and company, instead of just wasting billions of dollars in legal fees because people are suing you, you could have just asked me, and I would have explained the arachidonic acid pathway for you. Just kidding. This brings us to the end of the video. Thank you so much for watching. Don't forget to subscribe. There are 50 cases of hematology on my Patreon. Go to patreon.com/medicosis. Thanks for watching. As always, be safe, stay happy, and study hard.