Transcription
Hey guys, it's Medicos. Is perfection Ellis. Continuing our discussion about bleeding and coagulation disorders. In previous videos, we have talked about cyclooxygenase inhibitors, P2Y12 inhibitors, GPIIb/IIIa inhibitors. Today, I'll talk about phosphodiesterase inhibitors. With that being said, now let's get started and prevent platelet aggregation and blood coagulation. [Music]
First, let me summarize the antiplatelet drugs for you. First thing, we have the cyclooxygenase inhibitors, and since we are talking about the platelets, we're more concerned with cyclooxygenase-1 inhibitors. These are drugs such as aspirin, as well as the other nonsteroidals, but the aspirin is the hero here.
Next, we have the ADP receptor antagonists. They have another fancy name: P2Y12 inhibitors. And these are drugs such as clopidogrel, prasugrel, ticagrelor. Ticagrelor, the evil one, that's why we don't use it anymore, at least not often, and ticagrelor.
Then we have the famous GPIIb/IIIa inhibitors, and they include drugs such as abciximab, eptifibatide, tirofiban, and others. And then today's topic is the phosphodiesterase inhibitors, and these are the famous dipyridamole, as well as cilostazol. All crazy names. Let's just get this straight: when you have high levels of cyclic AMP in platelets, you have less platelet aggregation. We have low cyclic AMP, have increased platelet aggregation. That's why platelets hate that cyclic AMP, because it interferes with its mission and core purpose, because platelets love to aggregate and gossip about other people.
Cyclic AMP level in the smooth muscles of our artery, however, we have increased cyclic AMP, you have decreased vascular tone, which I call vasodilation. Same thing with increased cyclic GMP. So it depends on the tissue. For talking about the platelets, the higher the cyclic AMP, the lower the platelet aggregation. But if you're talking about the smooth muscles of arteries, the higher the cyclic AMP, the lower the vascular tone, or vasodilation. So same thing when cyclic GMP is high, other stuff is low. And I use red for low and green for high, just like the stock market.
Today's topic is the phosphodiesterase inhibitors. Let's say we have this ATP. Thanks to adding a light soy glaze, we have the cyclic AMP, because it's a cyclase. Then some enzyme is gonna digest this cyclic AMP into some pieces of trash. This enzyme is called the phosphodiesterase, and probably phosphatase 3. Well, so phosphodiesterase degrades the cyclic AMP. We're talking about phosphodiesterase inhibitors. There is nothing to degrade the cyclic AMP. The level of cyclic GMP in the blood is gonna rise. If you're talking about smooth muscle in the artery, you'll end up with vasodilation. We talk about the platelets, you'll end up with inhibiting platelet aggregation.
In my video about the difference between thromboxane A2 and prostacyclin, I've told you the mechanism of action of thromboxane A2. It's G protein-coupled receptor, Gi, it inhibits adenylate cyclase. So we have no cyclic AMP. When there's no cyclic AMP, there is more calcium, calcium coagulation. So increase of cyclic AMP equals decrease aggregation. Decreases in AMP equals increase platelet aggregation. When they go low, we go high. Dipyridamole or cilostazol, it's not the same drug, they are two drugs, but they are, they have the same mechanism of action. Cyclic nucleotide phosphodiesterase degrades the phosphodiester bond in cyclic AMP and cyclic GMP. This is the enzyme. It hydrolyzes this enzyme; in other words, it beats the living crap out of this thing into some piece of trash. So phosphodiesterase enzyme destroys cyclic AMP and cyclic GMP. Phosphodiesterase inhibitors inhibit this enzyme. No one is going to destroy the cyclic AMP, the cyclic GMP increased. Cyclic AMP and cyclic GMP, you have decreased platelet aggregation, as well as vasodilation.
Let me tell you again, dipyridamole, cilostazol, all phosphodiesterase inhibitors. No degradation of cyclic AMP and GMP. Increase of cyclic AMP and cyclic GMP. You end up with vasodilation, as well as decreased platelet aggregation. If your honor the platelets decrease with aggregation, guarantee smooth muscles of the artery you have decreased tone, vasodilation. This is what dipyridamole and cilostazol do.
Let's first talk about dipyridamole. What's the function? It decreases platelet aggregation. It causes vasodilation. So can we use it in thromboembolism prophylaxis? Yes. Why? Because it inhibits platelet aggregation and it increased vasodilation. If you remember my videos about hemostasis, hemostasis had many steps. Do you remember what was step number one? Yes, it was vasoconstriction. Vasoconstriction helps coagulation and clotting. When you vasodilate, you decrease the chances of primary and secondary hemostasis, thereby preventing blood clots. Medicine makes sense. Thromboembolism prophylaxis is needed in post-valve replacement. After they replace the valve, clots can gather on this valve, which is horrible. So we used dipyridamole for prophylaxis.
Next, we can use dipyridamole in cardiac stress test. Why? Because it's a coronary vasodilator. So what? Okay, let me tell you. So here is the famous classic chest pain patient. Patient comes in with chest pain. Doctor, I had chest pain yesterday, and I think I'm having a chest pain right now. You asked about the history and the characteristic of the pain. Can you tell me where the pain is? Point to the pain. Most patients who have chest pain don't have a heart attack, so they will describe it right; they will point with one finger to their left axilla, because most of the general population think that the heart is on the left. This is not true. The heart is in the center of the chest, just the ventricle is going a little to the left. But cardiac chest pain is central. The next thing is cardiac chest pain is poorly localized, so the patient cannot point to the pain just using one finger. The pain will use the entire hand like this, doctor, and the entire hand is on the center of this chest. That's an actual heart attack. How does the pain feel? It's as if an elephant is sitting on top of me. So is it sharp? No, no doctor, it's not sharp, it's dull, aching, heavy, squeezing pain, like an elephant sitting on my chest. That's an actual heart attack. So the patient is pointing with one finger, most of the time it's not a heart attack. If the patient is pointed to the left of this chest as the site of the maximal pain, it's not a heart attack.
So when you have this patient with chest pain, the first thing you do is you do the EKG or the ECG, whatever you want to call it, electrocardiogram. If the EKG is diagnostic and you see the ST elevation or whatever, we are done. You can send some labs for cardiac enzymes such as CK-MB and troponin, and this confirms your diagnosis. Please go ahead and save the patient's life. If the EKG is not diagnostic, then it depends. Can you exercise, sir? Can you run on a treadmill? Yes, I'm young, I'm like 40 years old, of course I can do it. Why are you talking about? I'm healthy as a horse, so why are you having chest pain? Okay, sorry, so I'll let you run on the treadmill. Oh, can you exercise, sir? Son, I'm a 60-year-old war veteran, and life is rough. I'm sorry, I can't, I can't even move. Can't you see it? Okay, okay, so we'll use something called dipyridamole thallium, or we can use Doppler, I mean, echo, echocardiogram.
Let's talk about dipyridamole thallium. There, dipyridamole, you inject the patient with dipyridamole to vasodilate the coronary. A normal heart should increase thallium uptake, because we are dilating the coronary, more blood supply to the heart, more power to the heart, therefore there should be more thallium uptake. If the patient is having a heart attack, you will find decreased thallium uptake, and this is diagnostic, or you can use dobutamine echo, dobutamine increasing the strength of the heart pump, and you'll see this on the echo normally. But if the patient has a heart attack, you'll find many stuff, and we'll talk about this in cardiology. The moral of the story is if the patient can't exercise and the EKG is not diagnostic, use dipyridamole thallium for cardiac stress test.
Now let's have some fun. Let's imagine that there is a patient coming to you and they have a knife in the left side of their chest and it's piercing the heart. Okay, then the patient is telling you, Doctor, I have a sharp pain. Sharp pain. Like I was told in medical school that cardiac pain is never sharp. RPR, yes, but in this case there is a knife in the chest. Okay, there's a knife inside the chest. Hello, of course it's gonna be sharp. Wake up, doctor. Can you point to the site of the pain, son? Yes, doctor, can't you see the knife is here? With one finger, I'm pointing, one finger. I was told in medical school that cardiac chest pain is poorly localized. Yes, doctor, but there is an exception. There is a knife in his freaking chest. Of course it's gonna be well localized, you idiot. So what should I do now? Should I like, use my fingers and my hand to remove the knife? Shut up, shut up. When a patient comes and there's a knife stuck to whatever place, you don't do anything. You get them to the operating room as soon as possible. It's an emergency right now, and this is the surgeon's job to remove the knife, because sometimes the knife can have a tamponade effect and it's blocking a disaster that's waiting to happen. If you remove the knife and a gush of blood came in your face and the patient died, you're an idiot. It's the surgeon's job. They will do it under anesthesia, under complete control. They have everything in sight and it's gonna be fine. Okay, so the knife is the only exception to the dull, poorly localized cardiac chest pain. And if you see this guy, he's pointing with the whole hand to the center of this chest, that's an actual chest pain. We're done with dipyridamole. Let's talk about the last one: cilostazol.
It's cilostazol. The "oral" US here being your mouth, not any other US, because there are many of them. Decrease platelet aggregation and causes vasodilation. Yep. Both aspirin and cilostazol are antiplatelet. Okay, we get it. Why? Because cilostazol is a phosphodiesterase-3 inhibitor. Increased cyclic AMP. When you have increased cyclic AMP, you have decreased platelet aggregation. Why is aspirin an antiplatelet? Because it's a cyclooxygenase inhibitor. When you inhibit cyclooxygenase, you have no thromboxane A2.
Medical uses of cilostazol: peripheral vascular disease, such as peripheral arterial disease. You have narrowing of the arteries in the periphery. Are there any arteries in the center? Yes. If you're talking about your heart, it's the coronary artery. Talking about the brain, it's the cerebral artery. But peripheral disease are arteries in the extremities. They are peripheral. Symptoms will include intermittent claudication. We give aspirin, we give cilostazol. Both of them are antiplatelet. Why? To prevent thrombosis, honey. But if you try cilostazol and it didn't improve the claudication after three months, you may stop it. Contraindications of cilostazol: CHF. Don't ever forget that. If the patient has congestive heart failure, do not give them cilostazol.
Side effects of dipyridamole and cilostazol: headache is the most common. I wonder why. Okay, headache is a very, very, very tough subject. Science has many theories and many opinions, but headache is usually traction or irritation of the meninges and blood vessels. Okay, this is where the nociceptors are. Nociceptors are pain receptors. And by the way, your brain itself doesn't feel pain. If I poke you with a needle into your brain tissue, you will not feel anything. If I poke you with a needle in your finger, you will feel pain. Why? Because there are nociceptors in your skin. There are no nociceptors in the brain. Exception is some meninges and some blood vessels in the brain, but the substance of the brain itself, like white matter, gray matter, they don't have nociceptors. And here is some Medicos' words of wisdom: the center of all pain sensations cannot feel pain. This is profound. Okay, back to cilostazol and dipyridamole. If they vasodilate the artery and this artery happens to be in your brain, of course you're gonna feel headache. Hello. And this is by far the most common side effect of these drugs. Also dizziness, diarrhea, facial flushing because of the vasodilation, increased heart rate, hypotension because of the vasodilation, also tachycardia because usually it's like reaction or reflex for the hypotension. You get tachycardia, leukopenia, and thrombocytopenia. If those drugs hate the platelet, maybe it's gonna decrease the platelet. Can decrease survival in CHF patients. That's why we do not use cilostazol in CHF patients. Don't ever forget that.
For A+ students, for the sophisticated among you, dipyridamole and cilostazol are phosphodiesterase-3 inhibitors. Therefore, increased cyclic AMP, because there is no one degrading it in the platelets. This means increase protein kinase A. If it's called the kinase, it means an enzyme. Kinase, like in English you might think kinetic, but in biochemistry, kinase means something that will add a phosphate group. So kinase is something that adds phosphate. But what about an enzyme that removes a phosphate group? That's gonna be the phosphatase, darling. So when you increase this protein kinase A, you have decreased platelet aggregation. And this is not just protein kinase A, it's the active form of protein kinase A. That's why dipyridamole and cilostazol inhibit platelet aggregation thanks to protein kinase A. Protein kinase A is in the muscles, or the smooth muscles of the artery. It decreases activation. Look at this name: myosin light-chain kinase. Kinase adds a phosphate group to the myosin light-chain to make it able to bind to actin, therefore muscle contraction. When you decrease the activation of the myosin light-chain kinase, you don't have muscle contraction, and therefore you have muscle relaxation in the wall of the artery. This is translated as vasodilation. And now you understand why dipyridamole and cilostazol are vasodilators and they inhibit platelet aggregation.
Cilostazol is metabolized by cytochrome P450 isoenzymes CYP3A4 and CYP2C19. Therefore, if you are taking P450 inhibitors, such as the famous grapefruit juice and others, it will inhibit the metabolism of cilostazol. No one is gonna metabolize cilostazol, so cilostazol level is gonna rise in the plasma. Therefore, you'll have increased toxicity and side effects of the cilostazol. So grapefruit juice can increase the toxicity of any drug that's metabolized by this system, including cilostazol. Drive sober, or get pulled over. Don't drink and drive, don't text and drive, and don't make a right turn without checking your blind spot, you idiot. And don't drink grapefruit juice while under the influence of cilostazol. Bad idea. Don't drink grapefruit juice, period. That's the joke. Okay, this is sarcasm, but it's hard to convince you. After all, you're the generation of the venti soy macchiato with fat-free white cream and no mocha drizzle. You are already confused. Why do I sound like grandpa even though I'm in my mid-20s? This is the question.
Now let's have a quick summary. In brief, dipyridamole and cilostazol are phosphodiesterase-3 inhibitors. Increase cyclic GMP, increase the active form of protein kinase A, decreased platelet aggregation as well as vasodilation. Uses: intermittent claudication, peripheral vascular disease, coronary dilation in stress test when you cannot read the EKG and the patient cannot exercise. Side effects: headache, flushing, tachycardia, hypotension. Interaction: P450 inducers and inhibitors. The inhibitors are many, including the famous grapefruit juice. Contraindications: don't ever give cilostazol to a patient with CHF. It decreases survival. If you love mnemonics, try Picmonic. They have great mnemonics in pictures. It's amazing for the visual learners among you. They have, they are especially good in pharmacology and microbiology. See the link in the description below.
Quiz time: what if you have a patient with peripheral arterial disease with intermittent claudication and a congestive heart failure? Which drugs should you give? Should you give cilostazol? If yes, tell me why. If no, tell me what else are you gonna give him to help them with intermittent claudication. I'll see you in the next video. Thank you guys for watching. Please subscribe and join the tribe. You can get my cases and my notes by going to patreon.com/medicos. Until next time, be safe, stay happy, and study hard.