Chapter 16: Antithrombotic and Thrombolytic Drugs

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Welcome back to The Deep End.

You are listening to a very special edition of The Deep Dive.

Today we are stripping away the noise and going straight to the source material for all our medical students, nursing students,

and hardcore pharmacology enthusiasts out there.

That's right.

We are metaphorically putting on our white coats today.

This isn't just a casual browse.

This is really a dedicated study session.

We certainly are.

Our mission today is to tackle one of the most high stakes, complex, and frankly just fascinating chapters in all of pharmacology.

We are diving into chapter 16 of Brenner and Stevens Pharmacology, sixth edition.

Yeah, the title is Antithrombotic and Thrombolytic Drugs.

It is.

And if that title sounds a little dry or technical to you, let me assure you the reality is anything but.

This is the stuff of life and death.

It really is.

We are talking about the delicate, um, razor thin balance that keeps your blood flowing, liquid enough to keep you alive, but solid enough to stop you from bleeding out when you get a paper cut.

Exactly.

It is a biological tightrope walk.

And when we intervene with drugs, we are essentially shaking that tightrope.

So this isn't just about memorizing drug names like warfarin or heparin.

No, not at all.

It's about understanding the why and the how.

So to get started, let's set the scope for everyone listening.

We're going to follow the progression of chapter 16 strictly.

Precisely.

We aren't going to wander off into other textbooks or clinical guidelines.

We'll start with the problem how clots form.

Then we will move to the drugs that prevent clots, which are the antithrombotics.

And after that.

And finally, the heavy hitters, the drugs that dissolve clots that have already formed the thrombolytics.

And before we get into the molecular nitty gritty, we should probably remind everyone why this matters so much.

The text highlights the big three cardiovascular disorders right there in the overview.

It does.

And for good reason.

You cannot work in medicine without seeing these constantly.

We are looking at myocardial infarction or MI.

Heart attacks.

Right.

Heart attacks.

We are looking at ischemic stroke and we are looking at venous thromboembolism, which includes deep vein thrombosis or DBT and pulmonary embolism or PE.

These are huge killers and the formation of intravascular thrombi clots inside the vessels.

That's the central villain in all of them.

It is the absolute central villain.

So to defeat the villain, we have to understand how the villain operates.

Let's set the scene with normal hemostasis.

This is figure 16 .1 in the text.

Can you walk us through what happens when I say, clumsily slice my finger while chopping onions?

What is the body's immediate reaction?

Okay.

Let's visualize this.

You slice the vessel, the body panics and immediately initiates four distinct steps.

Step one is vasospasm.

Vasospasm.

Yeah.

The blood vessel physically shrinks or constricts.

It's trying to reduce the flow to the area, literally pinching the straw shut to stop the leak.

Okay.

So step one is mechanical.

Pinch the pipe.

Simple enough.

Right.

Very simple.

Step two is the platelet plug.

This is where the platelets, those tiny little cell fragments floating in your blood, come into play.

Usually the lining of your blood vessels, the endothelium, is smooth and slick, but when you cut it, the collagen under the vessel wall is exposed.

And the platelets notice this.

They see that exposed collagen and go absolutely crazy.

They stick to it.

They get activated.

They change their shape and they start sticking to each other.

It's like a first response team.

Exactly.

It's like throwing sandbags into a breach in a levy.

They physically plug the hole.

This is what we often call primary hemostasis.

So we have a pile of sandbags, but sandbags can wash away if the current is strong.

They're not permanent.

Exactly.

That's why we need step three,

fibrin clot formation.

This is the cement.

The reinforcement.

The reinforcement.

The body actisates the coagulation cascade, which we'll get to in a second, to create fibrin.

Fibrin is this stringy protein that forms a mesh.

It wraps all around the platelet plug, traps red blood cells, and hardens the whole thing into a stable clot.

This is secondary hemostasis.

And once the danger is passed and the vessel starts healing, there's a final step, right?

Yes.

Step four,

fibrinolysis.

This is the cleanup crew.

Once the vessel is repaired, you don't want that clot sitting there forever blocking traffic.

It would be a problem.

So the body has a distinct, elegant system to dissolve the clot and remove it, restoring normal blood flow.

Okay.

So vasospasm, platelet plug,

fibrin clot, and fibrinolysis.

Now you mentioned the coagulation cascade.

I feel like this is the part where every student's eyes just glaze over.

It's figure 16 .2 and table 16 .1 in the book.

Can we make this not painful?

We can try.

It's actually quite elegant if you think about it.

Think of the coagulation cascade as a series of dominoes.

Okay, dominoes.

I like that.

You have these proteins called factors floating in your blood.

They're mostly serine proteases, which is just a fancy way of saying they're enzymes that cut other proteins.

But they're not always on.

No, usually they're inactive.

They're just dormant.

So factor X is just floating around minding its own business.

Until something wakes it up.

Exactly.

An already active factor comes along, cuts a little piece off the inactive factor, and boom, now that factor is an active enzyme.

And what does it do?

It goes and activates the next one in the chain.

And the text describes two ways to start this falling domino chain.

The intrinsic pathway and the extrinsic pathway.

What's the difference?

Why do we need two roads?

Well, the intrinsic pathway is triggered by surface contact like when your blood hits a foreign body or even the glass of a test tube.

So it's very important for lab work for tests like the APT we'll talk about later, but inside the body for our purposes.

And the text is very, very specific about this.

The extrinsic pathway is the star of the show.

The text notes it's the most important for in vivo coagulation.

Exactly.

In vivo means inside a living body.

The extrinsic pathway is triggered by something called tissue factor that's released from damaged cells.

So when I cut my finger, the damaged tissue screams help by releasing tissue factor.

This tissue factor grabs onto factor seven and that combination is what kicks off the entire chain reaction.

Okay.

So you have these two roads, intrinsic and extrinsic starting in different places.

Where do they meet?

Is there a convergence point?

There is, and it's crucial.

They merge at factor X.

If you remember nothing else about the numbers, remember X.

Factor 10.

Right.

Factor X is the rate limiting step.

It's the bottleneck.

It's the point of no return.

Once you activate factor X, you are heading to the finale.

And the finale is, what's the end goal of all this?

The end goal is thrombin.

Activated factor X or AZA as we call it, takes prothrombin, which is factor two, and converts it into thrombin.

And thrombin is the main event.

Thrombin is the director of the whole show.

It's the master enzyme.

Its main job is to take vibranogen, which is soluble, and just floating in the blood like liquid glue and chop it into fibrin.

Which creates that solid mesh we talked about.

The mesh.

The cement.

That's the final product.

But the book mentions a feedback loop here, right?

Thrombin isn't just a worker.

It's also a manager.

It's a hype man.

It's a system of mutual support.

Thrombin doesn't just make fibrin.

It also turns around and screams at the platelets to aggregate more, and it activates other factors upstream to speed everything up.

And the platelets?

The platelets, in turn, provide a surface for more thrombin to be generated.

It's a snowball effect, a positive feedback loop to ensure the bleeding stops fast and the clot is stable.

Okay, so that's normal.

That keeps us alive.

But this chapter is about when things go wrong.

We need to distinguish between the two types of bad clots.

Arterial and venous.

The book makes a huge point of this.

It is the fundamental concept for choosing your drugs.

If you don't get this distinction, you won't understand why we give aspirin for a heart attack but warfarin for a leg clot.

It's that important.

So break it down.

Let's start with arterial.

An arterial thrombus usually forms where there is high blood flow, fast moving blood, and it often forms on top of a ruptured atherosclerotic plaque -like cholesterol buildup in a coronary artery.

Okay, so a damaged part of the artery wall.

Exactly.

Because the flow is so fast, most of the coagulation factors, the dominoes, just get washed away before they can really accumulate and build a big fibrin mesh.

So what's left to stick?

Platelets.

The main thing that can stick and build up in that high flow environment is platelets.

So arterial clots are platelet heavy.

Precisely.

They're often called white clots because they are composed mostly of platelets.

That's why arterial clots cause heart attacks and ischemic strokes.

And that is why, as we'll see, we often treat them with anti -platelet drugs.

Makes sense.

Okay, now venous thrombi.

What's the story there?

Totally different environment.

Venous blood moves slowly.

It can pool, especially in the deep veins of the legs.

It's a low flow system.

Stasis.

Stasis.

That's the key word.

A clot in a vein, a DVT, is caused more by that sluggish flow, which allows all those coagulation factors to accumulate locally and go through their cascade.

So the fibrin mesh is the bigger problem here.

It's the dominant problem.

These clots are rich in fibrin and they trap a lot of red blood cells in that net.

They're often called red clots.

And these cause DVT and then, if a piece breaks off, a pulmonary embolism.

Correct.

And because they are fibrin heavy, we treat them with anticoagulants drugs that stop that fibrin mesh from forming in the first place.

Okay, that is a perfect transition.

Let's start with the anticoagulants.

Table 16 .2 in the text gives a great overview of these and we have to start with the classic, the grandfather of blood thinners, warfarin.

Warfarin, also known by the brand name Coumadin.

I love the origin story in the text.

This wasn't something designed in a fancy lab.

It started in a barn.

It really did.

It was discovered in the 1920s from spoiled sweet clover hay.

Cattle were eating this moldy hay and then dying of hemorrhagic disease.

They were just bleeding out spontaneously.

So they isolated the compound causing it.

They did.

And originally its first major use was as a rodenticide,

rat poison.

That's a ringing endorsement for medication.

Here, take this rat poison.

Well, the dose makes the poison, right?

Now, to understand how warfarin works, you have to understand vitamin K.

They are intimately linked.

Let's unpack the mechanism.

This is figure 16 .3 in the textbook.

Walk us through it in plain English.

So your liver makes four specific clotting factors.

You just have to memorize these.

Factors two, seven, I, X, and X.

Two, seven, nine, ten.

Right.

But when the liver first makes them, they're unfinished.

They're a little chemical tail to them.

It's a process called carboxylation.

And it needs a tool for that job.

It needs vitamin K.

Vitamin K is the essential cofactor for the enzyme that does that carboxylation.

Okay.

So vitamin K is the fuel for the activation machine.

Sort of.

Think of vitamin K as a rechargeable battery.

Every time it helps carboxylate or activate a clotting factor, the vitamin K gets oxidized.

It loses its charge.

It's spent.

So you need to recharge it.

You need to recharge it.

And there's an enzyme called vitamin K epoxide reductase.

That enzyme is the charger.

It takes the dead oxidized vitamin K and turns it back into active reduced vitamin K.

So it can be used again.

It's a recycling system.

And warfarin.

What does it fit in?

Warfarin unplugs the charger.

It directly inhibits that reductase enzyme.

So the vitamin K gets used once and then it stays dead or oxidized.

The liver rapidly runs out of active reduced vitamin K, and it can no longer activate new clotting factors.

It starts pumping out these dud factors that can't participate in clotting.

Now there's a weird quirk with warfarin's timing that the text really emphasizes.

It has a delayed onset.

It says it takes three to five days to really work.

Why?

If I take a pill now, why isn't it working in an hour?

This is a critical concept for students to grasp.

Warfarin does not kill or destroy the clotting factors that are already It's not an antidote to existing factors.

No.

It only stops the factory from making new functional ones.

So you have to wait for the old active factors that are already in circulation to die off naturally.

And they all have different half -lives.

Factor two, which is prothrombin, has a half -life of around 50 hours.

Wow.

So you have to wait days for those levels to drop enough to have a therapeutic effect.

Exactly.

You're just waiting for the old guard to retire.

That sounds really risky if someone has an active clot right now.

You can't just tell them to wait three days.

You can't.

It's incredibly risky.

That's why we use something called a bridge.

It's standard clinical practice.

If a patient comes in with a DVT, we start them on heparin, which works instantly, and warfarin at the same time.

So the heparin provides immediate cover.

It does.

We keep the heparin going for about five days until the warfarin has had time to kick in and the INR is therapeutic.

Then and only then do we stop the heparin.

That makes perfect sense.

Now, warfarin isn't without its risks.

Table 16 .3 in the text lists the adverse effects.

Obviously, bleeding is number one.

Yes.

Bleeding is the main adversary.

Any patient on warfarin is at risk for bleeding, and it can be anywhere, from the gums to the GI tract to the brain.

But there are other specific safety notes.

The book is very clear about pregnancy.

Absolutely contraindicated in pregnancy.

It's a teratogen.

It crosses the placenta and can cause something called fetal warfarin syndrome, which involves terrible bone and cartilage deformities.

Why the bones?

Because it turns out that some crucial bone matrix proteins also need vitamin K -dependent carboxylation to function properly, so warfarin messes that up too.

And then there are the drug interactions.

The list of drugs that interact with warfarin is massive.

It's a minefield.

It's one of the most difficult drugs to manage because of this.

Warfarin is metabolized by the CYP450 enzymes in the liver, particularly CYP2C9.

So anything that affects those enzymes will affect warfarin?

Anything.

If you take a drug that induces those enzymes, the text mentions refampin or barbiturates, your liver chews up the warfarin way too fast and the effect drops.

You might clot.

And reverse.

If you take a drug that inhibits those enzymes like erythromycin or the antifungal fluconazole, the warfarin can't be cleared.

The levels build up in your system.

The effect skyrockets, and you have a major risk of bleeding.

Even aspirin's a problem.

Yeah, that's a pharmacodynamic interaction.

Aspirin attacks platelets.

Warfarin attacks the fibrin cascade.

It's a double whammy on hemostasis.

Because of all this variance, we have to monitor our patients closely.

We use a blood test called the INR.

What is that?

It stands for International Normalized Ratio.

Basically, different labs used to get different results for the same blood sample when testing clotting time, which was dangerous.

So this standardizes it.

Exactly.

It's a math calculation based on the prothrombin time or PT test.

The text explains the formula, but the key for the student is to know the goal.

A normal person has an INR of about one.

And for a patient on warfarin, we usually target an INR of two to three.

If you have a high risk condition, like a mechanical heart valve, we aim even higher, maybe three to 4 .5.

And if the INR goes too high, if the patient is actively bleeding, what's the antidote?

First, you stop the drug.

Then you give the specific antidote, phytonadino.

Which is just fancy speak for vitamin K1.

Exactly.

You flood the system with fresh, usable vitamin K to overcome warfarin's blockade of the recycling enzyme.

For life -threatening bleeds, you might even give fresh frozen plasma or factor concentrates to replace the factors immediately.

All right.

Let's move to the other heavyweight champion of anticoagulation, the heparin family.

Heparin,

a totally different beast from warfarin.

First off, it's a huge molecule and it has to be given parenterally, usually for the infusion or subcutaneous injection.

Your stomach acid and digestive enzymes would just chop it up.

It wouldn't survive to be absorbed.

The mechanism here is fascinating.

Figure 16 .4 shows that heparin doesn't actually work alone.

It needs a partner.

No, it's a catalyst.

It needs a partner.

There is a protein floating in your blood called antithrombin the third, or AT3.

Its natural job is to inhibit thrombin and factorase A's, but usually it does it very, very slowly.

It's not very efficient on its own.

Not at all.

Heparin comes along and binds to AT3.

This binding causes a conformational change, a shape change, in the AT3 molecule.

It acts like a catalyst.

It gives it a superpower boost.

Exactly.

It makes AT3 about a thousand times faster at grabbing and inhibiting thrombin factorase A.

So heparin is the sidekick that makes the hero incredibly efficient.

But we have different flavors of heparin now.

We have the classic unfractionated heparin, then the low molecular weight heparins or LMWHs, and this other one, fondoparin X.

What's the difference?

It really comes down to molecule size, and because of that, it's specificity.

Unfractionated heparin is the old school natural form.

It's extracted from porcine intestine or bovine lung.

It's a mixture of big, long polysaccharide chains.

And because it's so long?

Because it's so long, it's able to wrap around and bind to both antithrombin and thrombin at the same time, forming a bridge that brings them together.

So it's great at shutting down thrombin.

It also shuts down factorase A.

Okay.

And the low molecular weight ones.

Right.

Like an oxaparin, brand name lovinox.

Those are just chopped up versions of unfractionated heparin.

They are shorter chains.

They're still long enough to bind to antithrombin and boost its activity against factorase A, but they are too short to effectively wrap around and bridge to thrombin.

So they have a much greater effect on inhibiting factorase A compared to thrombin.

And fondoparin X.

That is a tiny synthetic molecule.

It's just the essential five -sugar sequence, the pentasaccharide, that binds to antithrombin.

It's so small, it only activates antithrombin to target factor as it has zero effect on thrombin directly.

So why does this matter clinically?

Why do we care if it hits thrombin or zest?

Predictability and convenience.

Unfractionated heparin is messy.

It's big.

It binds to all sorts of other proteins in the blood.

So the effect is unpredictable from person to person.

You have to have the patient in the hospital and monitor them constantly with a blood test called the APTT.

The LMWHs are better.

Much better.

Their effect is very predictable.

You don't need to do routine monitoring.

You can just inject them subcutaneously based on patient's weight.

And it's great for outpatient use.

You can send the patient home.

That sounds like a huge advantage.

But heparin has this really spooky side effect called HIT, heparin induced thrombocytopenia.

Yes.

And it's something every student has to know.

There's type 1 HIT, which is mild.

The platelets just clump a little bit and the count drops, but it's not serious.

But type 2 is the scary one.

Type 2 is a disaster.

It's a serious immune mediated reaction.

The body, for some reason, makes antibodies against the complex of heparin and a protein on the platelet surface.

And what do these antibodies do?

Paradoxically, instead of just clearing the platelets, they activate them massively.

This causes widespread clotting all over the body in arteries and veins, which uses up all the platelets.

So you have this nightmare scenario of thrombosis and thrombocytopenia clotting and bleeding risk at the same time.

And if that happens?

You must stop heparin immediately, all forms of it, and switch to a different anticoagulant.

And if we need to reverse heparin, say a patient is bleeding from too high a dose.

We have a great antidote, protamine sulfate.

Heparin is an extremely negatively charged molecule.

Protamine is a highly positively charged protein.

You inject it, it binds to the heparin like a magnet, forming a stable in acts of salt and neutralizes it.

Simple chemistry saves the day.

Now, does it work for fonda perinex?

Less so.

The book notes it's much less effective for reversing fonda perinex, because the molecule is so different.

Okay, we have discussed the old guard warfarin and heparin.

Now let's talk about the newer drugs that have really changed the game.

The direct thrombin inhibitors and the direct factor Vaza inhibitors.

These are the DOACs, or direct oral anticoagulants.

They've been huge.

Let's start with the direct thrombin inhibitors.

The book mentions a few parenteral ones first, like bivaluridin.

Which comes from leeches, is that right?

It is.

It's a synthetic derivative of herudin, which is the potent anticoagulant found in the saliva of the medicinal leech.

That's wild.

It is.

Leeches need to keep blood flowing to feed, so they evolved this amazing inhibitor.

Bivaluridin binds directly to thrombin's active site.

It doesn't need antithrombin the third as a middleman.

We use it mostly during cardiac procedures like angioplasty.

And the text also mentions argotropin for a very specific situation.

Argotropin is often the go -to anticoagulant for patients who have developed HIT, since you can't give them heparin anymore.

But the real game changer was the oral one, davigatran, brand name Pradaxa.

The text calls this the first new oral anticoagulant in 50 years.

That was a monumental deal.

For decades, if you needed a long -term oral pill, you were stuck with warfarin and its dietary restrictions, its drug interactions, its constant blood tests.

And davigatran changed that?

It's an oral direct thrombin inhibitor.

It's a competitive, reversible inhibitor of thrombin.

It's a prodrug, davigatran atexalate, that your body converts to the active form.

And the benefits compared to warfarin.

The REALY study, which the text mentioned, showed it had lower rates of stroke and major bleeding.

But the real clinical benefit was the convenience.

No routine INR monitoring, no major food interactions.

But it has its own issues, right?

It's cleared by the kidneys.

Yes.

That's its Achilles heel.

You have to be very careful in patients with kidney failure, as the drug can accumulate to dangerous levels.

And for a long time, doctors were scared to use it because if a patient did bleed, there was no antidote.

That was the big fear.

If you bled on warfarin, we gave vitamin K.

If you bled on davigatran, you just had to support the patient and wait.

But now, as the text notes, we have a specific reversal agent.

Iduracizumab, brand name Praxbind.

And what is that?

It's a monoclonal antibody fragment that binds to davigatran with incredibly high affinity and neutralizes it instantly.

It's a true designer antidote.

Science is amazing.

Now,

the other huge group of oral drugs.

The direct active factor ZE inhibitors.

The ABENS.

Riveroxaban, apixaban, adoxaban, betrixaban.

These all end in ABEN, which is your clue.

They inhibit factor ZE.

And their mechanism.

They bind directly to the active site of factor ZE.

They just sit in that pocket and block it.

This stops the cascade right at that convergence point, preventing the conversion of prothrombin to thrombin.

What are they used for?

Huge usage now.

They've largely replaced warfarin for preventing stroke in nonvalvular atrial fibrillation.

They're used for treating DVT and PE.

And for preventing clots after major orthopedic surgery like hip or knee replacements.

And again, the pros are similar to davigatran.

Oral fixed dose, no monitoring.

All the same conveniences.

But again, bleeding is the major risk.

Always.

It's the price you pay for anticoagulation.

And for a while, just like with davigatran, we had no specific antidote.

The book mentions that a universal antidote and dexanet alpha was in development.

For severe bleeds, we often have to use prothrombin complex concentrates to just try and overwhelm the drugs effect.

Okay, we have covered the anticoagulants, the fibrin fighters.

Now we need to shift gears to the antiplatelet drugs.

These are the drugs for the arterial side of the story.

For heart attacks and strokes.

Right.

We are moving from the fibrin mesh to the platelet plug.

Figure 16 .5 is the key mac here.

It shows a diagram of the platelet with all its important receptors and signaling pathways.

So let's visualize the platelet again.

It's floating along and it sees exposed collagen.

It sticks.

What happens next?

Okay, so it adheres using specific receptors.

Then it gets activated.

And an activated platelet is like a communications hub.

It releases a bunch of chemical mediators from its granules.

And what are the big ones we need to know?

The two huge ones are thromboxane A2 or TXA2 and ADP.

These are the signals that scream, everybody pile on to all the other platelets floating by.

So they're recruitment signals.

Exactly.

And the final step of aggregation, the thing that actually links platelets together, happens when a receptor called the GP IAB receptor changes shape and grabs onto fibrinogen, which acts like molecular glue, linking one platelet to the next.

So the anti -platelet drugs target these specific steps.

Let's start with the most famous one of all, aspirin.

Aspirin.

It's been around forever, but its mechanism is really clever.

It irreversibly inhibits an enzyme called cyclooxygenase or COX, specifically TOX1 in platelets.

And what does that do?

By inhibiting TOX1, it completely shuts down the platelets ability to produce gromboxane A2.

So it takes away one of those key recruitment signals.

But the text mentions a balance issue with aspirin dosage.

This is a really high yield point.

It is fascinating.

So the COX enzyme in the cells lining your blood vessels uses the same pathway to make something called procycline or PGI2.

And procycline is a good guy.

Procycline is a good guy.

It's a vasodilator and it inhibits platelet aggregation.

It's the natural counterbalance to thromboxane A2.

So you don't want to block that.

You don't.

And here's the clever part.

Platelets are just cell fragments.

They don't have a nucleus.

When aspirin irreversibly kills their COX enzyme, they can't make any more for their entire lifespan.

But the endothelial cells lining your vessels do have a nucleus.

They can just synthesize new COX enzyme.

So a low dose of aspirin.

A low dose is enough to knock out the platelet COX for good, but it only temporarily affects the endothelial cells, which can recover.

This tips the balance in favor of the anti -clotting prostacyclone.

That's why we give baby aspirin, 81 milligrams, for heart protection, not high doses.

Right.

Okay.

Next up, the ADP inhibitors, also called P2Y12 inhibitors.

The most famous is glopidogrel or Plavix.

Right.

These drugs block the P2Y12 receptor.

That's the receptor on the platelet that recognizes ADP.

If ADP can't bind, the platelet doesn't get that second key activation signal.

And there are a few different kinds.

Yes.

Clopidogrel and prashagrel are irreversible blockers.

Ticagrelor and kangrelor are reversible.

They're used all the time in patients with acute coronary syndromes, or after getting a stent, to prevent the stent from clotting off.

And clopidogrel is another one with a big genetic and drug interaction warning in the text.

It is.

This is another really important clinical pearl.

Clopidogrel is a prodrug.

It's inactive when you take it.

It needs the liver enzyme CYP2C19 to convert it into its active form.

And the problem is?

Well, a significant portion of the population has genetic variants that make this enzyme less active, so for them, the drug doesn't work well.

Also,

common heartburn medications, the proton pump inhibitors like omeprazole, are potent inhibitors of CYP2C19.

So if you take omeprazole with your plavix...

You might be effectively taking a sugar pill.

The plavix may never get activated to do its job.

It's a huge potential issue.

That is a huge clinical pearl.

Okay, the last group of antiplatelets are the real heavy artillery.

The GPIV antagonists.

These are the big guns.

They block that final common pathway, the binding of fibrinogen to the GPIV IR receptor.

If you block this, it doesn't matter how much thromboxane or ADP is around.

The platelets simply cannot stick together.

They are the most powerful antiplatelets we have.

The drugs themselves are eclectic.

The texilis avziximab.

That's the fab fragment of a monoclonal antibody.

Very high tech.

And heptafibritide.

This one has a great story.

It's a cyclic heptapeptide that was designed based on a protein found in the venom of the southeastern pygmy rattlesnake.

Of course it is.

From spoiled hay to leeches to snake venom.

Pharmacology is wild.

It really is.

These are IV -only drugs.

And because they're so potent, we only use them in high -risk situations, like during a complex angioplasty, to prevent acute clots from forming right on the stent.

Okay, so we have prevented the clots with anticoagulants and antiplatelets.

But what if the clot is already there?

What if the patient is having a massive heart attack or stroke right now?

That's when we bring in the thrombolytics.

It's clot busters.

How do they work?

The mechanism is in figure 16 .6.

It's elegant.

The body has its own natural clot buster system.

There's a pro -enzyme called plasminogen that gets incorporated into the fibrin clot as it forms.

These drugs work by converting that inactive plasminogen into its active form, plasmins.

And what does plasmin do?

Plasmin is the enzyme scissors.

Its job is to cut up the fibrin mesh into little pieces, called fibrin degradation products.

It literally dissolves the clot from the inside out.

We have a few different types, the TPA derivatives like alteplase and tenectoplas, and then there's an older one, streptokinase.

Right.

Streptokinase is a protein that comes from streptococcal bacteria.

It's older and less specific.

It activates plasminogen everywhere in the body, not just at the clot, so it tends to deplete your clotting factor system -wide and cause more bleeding.

You can also have an allergic reaction to it.

Whereas the TPAs, the tissue plasminogen activators, are fibrin specific.

They are.

They preferentially activate plasminogen that is already bound to fibrin within a clot, so they are more targeted, in theory, leading to less systemic bleeding.

The key with these drugs is time.

The book stresses this.

Time is muscle for the heart.

Time is brain for a stroke.

Absolutely.

For a heart attack in MI, you want to give these drugs within six hours of symptom onset if you can't get the patient to a cath lab for an angioplasty.

For an ischemic stroke, the window is even tighter, generally 3 to 4 .5 hours.

And there's a critical safety step for stroke.

You absolutely must get a CT scan of the head first to rule out a hemorrhagic stroke, which is bleeding in the brain.

If you give a clot buster to someone who is actively bleeding in their brain, you will almost certainly kill them.

And what if we cause too much bleeding with these clot busters?

Can we reverse their effect?

Yes, we can.

We use drugs like aminocoproic acid or tranexamic acid.

These are lysine analogs.

They look like the amino acid lysine.

And how does that help?

They work by binding to plasmin and blocking the site it would normally use to bind to fibrin.

They basically handcuff the scissors so they can't cut the clot anymore.

Let's pull all of this together.

The text provides a fantastic case study in box 16 .1.

It's a 61 -year -old man who comes to a community hospital with crushing chest pain.

This is a classic stemmian ST elevation myocardial infarction, a complete blockage of a coronary artery.

Let's look at the cocktail of drugs they give him.

First up, aspirin, 325 mg, chewed.

Chewed for rapid absorption.

That's to immediately inhibit thromboxane A2 and prevent any more platelets from piling on.

Next, they give him nitroglycerin.

That's to dilate the coronary vessels and try to improve blood flow and relieve some of the pain.

Then he gets a loading dose of clopidogrel and an injection of anoxaparin.

A double whammy.

The clopidogrel is an ADP blocker, so we're hitting the platelets from a second angle.

The anoxaparin is a low -molecular -weight heparin.

That's to shut down the coagulation cascade at factor ZA so the fibrin mesh doesn't get any bigger.

And finally, because this hospital didn't have a cath lab for angioplasty, they give him the big one,

tenecteplase.

The thrombolytic.

The clot buster.

That's the drug that is going to go in and actively dissolve the blockage that is killing his heart muscle.

Wow.

That is the whole chapter in one patient.

It perfectly illustrates how these different drug classes are layered and work together.

It really does.

Antiplatelets to stop the trigger,

anticoagulants to stop the growth, and thrombolytics to destroy the existing blockage.

It's a beautiful example.

All right.

Before we let our listeners go, let's test their retention.

I'm going to throw a couple of the review questions from the end of the chapter at you and at them.

I'm ready.

Let's do it.

Okay.

Question one.

Which of the following drugs is a reversible fibrinogen antagonist at GP IVO receptors?

Is it prosugural, rivaroxaban, or eptifybotide?

Let's see.

GP IVO antagonist.

That would be eptifybotide.

The snake venom derivative.

It blocks that final receptor for fibrinogen, and it's reversible.

Correct.

Okay.

Question two.

Which of the following is an orally administered inhibitor of active factor X used to prevent DVT?

Is it dabigantran rivaroxaban or inoxaparin?

Okay.

Orally administered inhibitor of factor X.

That's got to be rivaroxaban.

The clue is in the name.

Rivaroacaban.

Dabigantran hits thrombin, and inoxaparin is an injection, not oral.

Look at you, nailing the test.

Two for two.

I read the chapter.

So, as we wrap up, what's the big picture here?

What's the final thought we should leave everyone with?

You know, it brings me back to that thought we started with about the war between clotting and a system that was designed over millions of years to save us from bleeding to death.

A system that's essential for survival.

Absolutely.

And we're manipulating it to save us from clotting to death.

If we clot too much, we die of a heart attack or stroke.

If we don't clot enough, we die of a hemorrhage.

These drugs, from the crude ones discovered in spoil hay like warfarin, to the designer antibodies like aderutizumab, are our way of trying to put a thumb on the scale of that delicate balance.

And the balance is razor thin.

It is.

It's incredibly thin, and it demands our respect and our understanding.

Absolutely.

It's a powerful reminder that medicine is all about precision and understanding the why.

So, to all the students out there, review those tables in chapter 16.

Draw out that coagulation cascade until you dream about it.

It will pay off.

And remember, keep your platelets happy, but not too sticky.

Thanks for listening to this last -minute lecture on the deep dive.

Good luck with your studies.

Goodbye, everyone.