Transcription
It's a series of lectures about bleeding and coagulation disorders. In the previous video, I talked about the P2Y12 receptor, which is a receptor on the platelet, and it's a receptor for ADP. Today, I'll talk about the P2Y12 receptor inhibitors. A great video, and now let's get started. [Music]
Platelet receptors are proteins, and they are part of the glycoprotein coat on the outside surface of the platelets, and the P2Y12 is no exception. Your great cell membrane is made of protein, among others, so membrane proteins are either integral or peripheral. Most receptors are peripheral proteins.
Hemostasis has many steps. Temporary platelet plugs, also known as primary hemostasis. When we talk about the P2Y12 receptor, we're talking about the temporary plug or primary hemostasis. When we talk about P2Y12 inhibitors, we are talking about inhibiting primary hemostasis. I hope this is clear. If you have problems understanding the platelet plug or primary hemostasis, please watch this great video about a mnemonic; it's in the playlist. Adhesion, activation, aggregation. First adhesion: have GP1b; it's a receptor on the platelet. Adhere to the von Willebrand factor, which is bound to the subendothelial collagen. Okay. Then platelet activation by secreting ADP and thromboxane A2. ADP is a great whistleblower, and it will cause ADP-dependent expression of GPIIb/IIIa receptor. But it's more complicated than that. Here's the real story: ATP will bind to the receptor, such as P2Y12 receptor on the platelet. Then GPIIb, then—I'm sorry—P2Y12 receptor will transform this GPIIb/IIIa from inactive form into the active form via a conformational change, which means a change in shape. After this, GPIIb/IIIa is active and ready to bind other platelets. A molecule of fibrinogen is present in between, and then fibrinogen will be converted into fibrin, and this will be the secondary hemostasis, also known as the thrombus, also as the coagulation cascade.
P2Y12 receptor is a receptor on the surface of platelets, made of protein, of course, because most receptors are proteins, if not all receptors. One of the 12 types of purinergic receptors, from 1 to 14. P2Y1 is GQ coupled; P2Y12 is GI coupled. What's the function? P2Y12 promotes platelet aggregation, and if you have platelet aggregation, you have a great path towards blood coagulation. If you don't have platelet aggregations, in cases when you use P2Y12 inhibitors, such as clopidogrel, no platelet aggregation, no blood coagulation; it's not going to happen. If there is no platelet aggregation, in vain there is blood coagulation. Parts of my words of wisdom: P2Y12 is a chemoreceptor for ADP. So here is ADP; like here, here is the P2Y12, a receptor for ADP. Okay, fine. Then, since it's GI coupled—I for inhibitory—it's gonna inhibit the level of cyclic AMP. When you have low cyclic AMP, you are ready to convert this GPIIb/IIIa from inactive form into the active form. If GPIIb/IIIa is active, platelet aggregation is gonna happen. So when we talk about P2Y12 inhibitors, they inhibit the activation of GPIIb/IIIa; they inhibit platelet aggregation, and therefore they inhibit blood coagulation. The good news is this class of medications can prevent thrombosis. The bad news is you're more likely to bleed, because there are no solutions in life, only trade-offs.
GI coupled prevents the conversion of ATP into cyclic AMP. You remember the enzyme adenylate cyclase. When you have low cyclic AMP, you have more calcium; more calcium, more coagulation. Calcium coagulation. So when cyclic AMP is high, platelet aggregation is low; when cyclic AMP is low, platelet aggregation is high. When they go low, we go high. So how does that P2Y12 work? It's a GI coupled receptor, decreasing cyclic AMP, promoting platelet aggregation. How does the P2Y12 inhibitors—the medication—work? They inhibit the P2Y12, which is a GI coupled; no decrease in cyclic AMP, no increase in platelet aggregation. Makes perfect sense. Medicine is a piece of cake if explained properly, which is kind of rare these days, because most professors are in it; they are more concerned about who is following them on Instagram than about delivering a precise, neat piece of lecture.
ADP, P2Y12, which is a receptor for ADP; it's GI, for inhibitory; it inhibits the conversion of ATP to cyclic AMP. Low cyclic AMP, more calcium; you can now convert this GPIIb/IIIa from the inactive form into the active form. Hey, we have platelet aggregation. Let's add some medications which are P2Y12 inhibitors, such as clopidogrel, prasugrel, ticagrelor, and ticagrelor. Or now we have no GI; you have no decrease in cyclic AMP; in fact, you'll have increase in cyclic AMP; okay, decrease in calcium; no conversion of GPIIb/IIIa into the active form; no platelet aggregation, because when cyclic AMP is high, platelet aggregation is low.
P2Y12 receptor inhibitors are clopidogrel, prasugrel, ticagrelor, and ticagrelor. Let's start with clopidogrel. It's used together with aspirin; no kidding, because aspirin is antiplatelet. How? By inhibiting the cyclooxygenase, and we were talking platelets; we're talking specifically about the cyclooxygenase-1. When you have no cyclooxygenase-1, you have no thromboxane A2. Okay, you remember the two whistleblowers? Yes, thromboxane A2 and ADP. As for heavies, thromboxane A2. Clopidogrel inhibits ADP from binding to the great receptor, P2Y12, and this is the whole story. Morning glory. Aspirin plus clopidogrel is a powerful combo, because not only McDonald's have combos, doctors and hospitals have combos as well, except our combos are very expensive; we do not charge you $5.95. This combo is called dual antiplatelet therapy, used for heart attacks, yeah, because in heart attacks you have a clot in your coronary artery. This is a bad coronary. Okay, if you have a clot in your coronary artery, you can have a heart attack because there's no oxygen supply to the whole. Clopidogrel and aspirin can prevent that. Coronary arteries 101. Okay, sometimes your coronary artery is blocked, so we introduce like a catheter or a stent into your coronary artery to poke it and open it and destroy the clot. However, after the surgery is done, sometimes you can clot the stent, which is kind of like your very unfortunate. Okay, here comes the clopidogrel and aspirin to prevent the clogging or the clots from forming inside the stent. These drugs can prevent ischemic stroke. So instead of the heart, if this is your brain, and instead of a coronary artery you have a cerebral artery, same thing here; a clot can form in this artery, causing an ischemic stroke, because we have two types of strokes: ischemic and hemorrhagic. When there is a clot in the artery, we call this an ischemic stroke. Route of administration of this clopidogrel is PO, which means oral, and the PO here being your mouth, not any other awesome. Okay. Onset: two hours. It's a prodrug, which means it requires metabolism first in order for it to become active. Mechanism of action is a P2Y12 inhibitor, and this is a non-competitive inhibitor; this is irreversible inhibition. If the patient is allergic to aspirin, use clopidogrel. It's a prodrug, activated in the liver by the CYP2C19, member of the cytochrome P450 system. Adverse effects: bleeding, of course; inhibit spoilers. TTP. Wow. Rash and sensitivity. Drug interaction may include other drugs that are inducers or inhibitors of the CYP2C19, member of the P450 cytochrome system. If you love mnemonics, try Picmonic; a picture in a mnemonic, or a mnemonic in a picture, or whatever. And they have a Picmonic about clopidogrel, which is today's topic. This company is awesome, and see the link in description below; they are not a sponsor of this video; I just recommend. We're done with clopidogrel; let's go to the next guy: prasugrel. Together with aspirin for acute coronary syndrome, which is an umbrella term that includes three things: unstable angina, non-ST elevation myocardial infarction, or non-ST elevation, and ST-elevation myocardial infarction; non-STEMI and STEMI. Percutaneous coronary intervention to keep the stent open, as we have discussed with clopidogrel. It's a prodrug; same as clopidogrel. It's more effective than clopidogrel; however, there's more risk of bleeding, because this is life; if you inhibit the platelets more, you're gonna bleed more. In life, there are no solutions, only trade-offs. Side effects: bleeding. Contraindications: if you have active bleeding; if I have a hemorrhagic stroke, please don't give a drug that will make you bleed. This is known as stupid.
Clopidogrel, prasugrel, ticagrelor, or ticagrelor is the evil one. Ticagrelor, believe it or not, was the first P2Y12 inhibitor in history. This was the first drug invented, by the way. There is no difference between saying a P2Y12 inhibitor and an ADP receptor antagonist, because as you know, P2Y12 is the ADP receptor. So if you have a question on your exam and they are asking what's the mechanism of action of clopidogrel, prasugrel, ticagrelor, ticagrelor, or whatever, and you have among the choices ADP receptor antagonists, choose it. If you don't find it, don't panic; choose the P2Y12 receptor inhibitor. Just common sense, guys. Why do we call ticagrelor the evil one? Because there is risk of life-threatening hematological toxicity, such as agranulocytosis, as well as thrombotic thrombocytopenic purpura. What the flip is agranulocytosis? A, in Greek, means no; granulocytes; osis means condition; it's a condition when you have no granulocytes. You need some etymology and terminology. Okay, here we go. Why do we call anatomy anatomy? Tomy means to cut, like a knife; ana means up; so literally, anatomy means to cut you up. Don't forget, tomy means cut. How about atom? A means no, and tell me in Scott, atom is the thing that you cannot cut down into pieces; it's the building unit of matter, at least at that time. What's the actual building unit of matter? I'll leave this to the great chemistry professors. Back to agranulocytosis: the condition with no granulocytes. What the flip are the granulocytes? They are three cells: they are eosinophils, basophils, neutrophils. You know, phils. Neutrophils. When you're taking this garbage drug, you are risking decreasing these cells in your body; those are white blood cells. When you have no white blood cells, you're more liable to infections. What else? Thrombocytopenia, TTP, aplastic anemia, which is a wrong name; the correct name should be aplastic pancytopenia, because you have decreased red blood cells, decreased white blood cells, and decreased platelets. The best name is aplastic pancytopenia. Therefore, if you are giving a patient ticagrelor, clopidogrel, or prasugrel, or ticagrelor, please check the complete blood count frequently to check for agranulocytosis, TTP, and/or aplastic anemia, which is not anemia; it's a pancytopenia. And that's a great question. You might have a board question on your exam, and you have like a patient taking clopidogrel or ticagrelor, and the question is: which of the following should be done frequently? And one of the answers: measure the CBC frequently. And this is the correct answer. Why? Because we have agranulocytosis, aplastic anemia as side effects.
Ticagrelor, tradename Brilinta, and this is a great name, by the way. If I have a daughter, the first daughter is gonna be Malassezia, because I love the great Malassezia furfur fungus, and the second daughter will be named Brilinta, because I love P2Y12 inhibitors. Vampires are history; P2Y12 inhibitors is the new thing, if you know what I mean. Users of ticagrelor: prevention of strokes and heart attacks, of course. Adverse effects: shortness of breath, bleeding, no kidding; ventricular pause; wow; and allergy. Contraindications: if the patient is actively bleeding and CYP3A4 inhibitors, because this ticagrelor is metabolized by this enzyme, CYP3A4, which is a member of the cytochrome P450 system in your liver. So if you are taking a CYP3A4 inhibitor, such as like grapefruit juice, for example, grapefruit juice inhibits this enzyme. When you inhibit this enzyme, no one will metabolize ticagrelor; ticagrelor will float in the plasma freely, with no one to break it down. This will increase ticagrelor toxicity, increasing your risk of bleeding. Don't drink and drive; don't text and drive; and don't take ticagrelor while on grapefruit juice.
Influence. Now let's have some fun. Here are the P2Y12 receptor inhibitors, also known as ADP receptor inhibitors: clopidogrel, prasugrel, ticagrelor, ticagrelor. What's the mechanism of action? They are P2Y12 inhibitors, aka ADP receptor antagonists. Prodrug? Yes, yes, yes, no. Ticagrelor is already active. If it's a prodrug, it's not an active metabolite. If it's a prodrug, it's not an active metabolite; it's a prodrug; it's not an active metabolite. But it's not a prodrug; yes, it's active. At least this is how I remember it. Metabolism, or how does the drug become active? Except ticagrelor, because it's already active. So this one needs CYP2C19; CYP3A4; CYP2C19; CYP3A4. So tuk tuk tuk tuk; the alternate CYP2C19, then this, then CYP2C19, then this. All of these are members of the cytochrome P450 system in your liver.
Some notes: clopidogrel used together with aspirin for prevention of thrombosis after placement of coronary stent, which is part of a percutaneous coronary intervention; #keepthestentopen. Slow metabolizers have no effect. Prasugrel: good for patients undergoing PCI; same thing. Possible adverse effect is life-threatening bleeding, because it's more efficient and effective than clopidogrel. Ticagrelor is the evil one; why? It can cause life-threatening hematological toxicities, such as agranulocytosis or neutropenia, aplastic anemia, and TTP; sorry, I meant aplastic pancytopenia. Check the CBC. Prasugrel. When you give it with aspirin, this is called synergy in pharmacology; synergy, when one plus one equals more than two. In mathematics, this is called stupid, but in pharmacology this is called synergy. We use ticagrelor for patients with acute coronary syndrome, which is an umbrella term that includes unstable angina, non-STEMI, and STEMI, as well as post-MI as maintenance therapy. All of these drugs inhibit the ADP receptor; they inhibit platelet aggregation, but they have a side effect of bleeding. If you have a patient who is scheduled for surgery, please stop all of these drugs at least 5 days before the surgery. Again, talk to your surgeon, because everybody is different.
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