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How Do ALL IA Drugs Work | Interventional Stroke Therapy - Part 1
How Do ALL IA Drugs Work | Interventional Stroke Therapy - Part 1
2012alteplasearterialarteriesarteriolararterybacteriasdesigneddilatationdosedosingdrugdrugsendotheliumexcretionfibrinflowshypotensionneuroprotectantocclusionsperiodprolongedrenalserumsystemicUHNvenousverapamil
Atherothrombotic Occlusion and Thromboembolic Occlusion | Interventional Stroke Therapy - Part 1
Atherothrombotic Occlusion and Thromboembolic Occlusion | Interventional Stroke Therapy - Part 1
2012activationembolusfibrinocclusionocclusiveplaqueplateletsrupturedstrandstherapytypicalUHN
Plasmin Dissolves Clots - Lytics Are Catalysts | Interventional Stroke Therapy - Part 1
Plasmin Dissolves Clots - Lytics Are Catalysts | Interventional Stroke Therapy - Part 1
2012activateagentfibrinlysislyticsmilligramocclusionsplasminplasminogentpaUHN
Plasminogen Activators - tPA  | Interventional Stroke Therapy - Part 1
Plasminogen Activators - tPA | Interventional Stroke Therapy - Part 1
2012bindsclearedfibrinlysisplasminserumthrombustpaUHN
Current IV tPA Dose Usage - Structure and Activity of Reteplase | Interventional Stroke Therapy - Part 1
Current IV tPA Dose Usage - Structure and Activity of Reteplase | Interventional Stroke Therapy - Part 1
2012activasealteplaseclotconcentrationdosedrugflowlysisrangingreteplasespeedUHN
Binding of Alteplase and Reteplase to Clots and Urokinase  | Interventional Stroke Therapy - Part 1
Binding of Alteplase and Reteplase to Clots and Urokinase | Interventional Stroke Therapy - Part 1
2012clotdirectlydrugfibrinintravenouslypenetratesreteplaseUHNurokinase
Implications and Optimal Doses | Interventional Stroke Therapy - Part 1
Implications and Optimal Doses | Interventional Stroke Therapy - Part 1
2012dosesfoldlysisoncologyoptimalrabbitreteplasestudiesUHN
Serum Level from Oncology Journals | Interventional Stroke Therapy - Part 1
Serum Level from Oncology Journals | Interventional Stroke Therapy - Part 1
2012dosedruglysisoncologyoptimaltpatrialtumortypicalUHN
FLASH - Micro Filter for tPA and Reteplase | Interventional Stroke Therapy - Part 1
FLASH - Micro Filter for tPA and Reteplase | Interventional Stroke Therapy - Part 1
2012airair filteralteplasefilterfilteredmicrocathetersreteplasetpaUHN
Transcript

I'm Dr. Buddy Connors. Today we're going to be talking about drugs necessarily to know for the treatment of stroke as well as pre and post treatment of stroke so that you'l understand the entire spectrum of the pharmaceuticals necessary for management of patients. This is going to cover things to help you with preventing mistakes that can happen during stroke therapy, as well as to improve your outcomes. Some things to know right off the bat, and that is that

the perfusion of the brain is related directly to how much blood gets to the brain. Most of the brain is supplied by approximately 50 cc/100 gm/min to brain tissues that varies a little bit between grey matter, and white matter. Brain function's normally down to about 20 cc/100 gm/min. But once you get below that, electrical activity gets disrupted, and you start having

symptoms. However when you get down to about 10 cc/100 gm/minute you start having neuronal death, and at this point that's when a stroke occurs. If you have pure cardiac arrest, you drop to 0 cc/100 gm/min, and you get cell death within three to five minutes. So when you're around 10 you can hang on for a little while, between 10 and 20 you can hang on for a little bit

longer, and those are the areas where you will have severe symptoms with incipient death, and that's why rescue of brain cells is more important the faster you go. A basic understanding of how we do intra-arterial treatment of any kind is how do all of these intra-

arterial drugs work. Most drug dosing when they're handed out in the package insert is based on a systemic effect. They measure

what the typical serum level is, and it's weight based, and the serum level is determined by the half-life, whether it's renal excretion or hepatic metabolism. The drug circulates throughout the body for a continual period of time, and it touches whatever cells it need to touch such as antibiotic touches bacteria. And it flows around, and touches these bacterias over a period of time,

and slowly has more, and more influence on the bacteria. The same thing with renal cells, the same thing with prostaglandins. But none of these drugs really work instantly or even kill instantly, but there are some drugs that do have a rapid effect. For intra-arterial use, if we just blast a drug through an arterial bed it immediately gets to the venous bed where the drug then becomes just a systemic

drug. So there is no point in giving an intra-arterial drug unless we want to affect the exact place it's going through. So a bolus gives a very short period of time where we're getting an effect on the endothelium of the artery itself or whatever is in the artery that we're trying to affect. Therefore the most strategic plan for using drugs intra-arterially is to give them over a slightly longer

period of time. So that it bathes the arteries themselves in the drug or whatever happens to be in the arteries such as thrombus. Certain drugs however do work in a slightly different manner. Certain drugs give immediate paralysis of such things as muscles or arteriolar muscles, and media of the blood vessels, and one such would be Nitroglycerin. It works extremely rapidly, you can give it in a bolus, and it

gives a quick effect. There's other drugs that have a stick and stay type of action, such as alteplase. Alteplase, was designed specifically to go, and stick to a particular type of cell, and stay there, and do it's work, these drugs are tailored specifically for intravenous use. Most drugs however, work by circulating, and repeatedly touching whatever membrane it is they're designed to

touch. For intra-arterial use, what we're trying to do is to get a very high local concentration by delivering it intra-arterially, and a prolonged contact will give more, and more benefit. One such example of this is verapamil. Verapamil does not give an instant effect such as Nitroglycerine, and therefore a slower, and longer delivery of this drug allows this to bathe the endothelium of the vessel

better than if we gave in a very brief bolus. If we give it in a bolus, it flows through the arteries, and into the veins, and then you get a systemic effect. If you give a large enough dose intra-aterially, you get a little bit more than intra-aterial effect. You get more arterial vasodilatation, but you also get dilatation all through out the body because you've a given it a systemic dose

of the drug itself. And therefore that gives you hypotension, and the hypotension itself, it counteracts the effect your trying to get with the vasodilatation. So therefore the best effect for verapamil without getting systemic hypotension, is to use less than a systemic dose, but give it over a more prolonged period of time in the arteries themselves. I already talked about alteplase, this is a custom

designed drug that actually sticks to the target because it is fibrin specific, and fibrin adherent. No other drugs really do that other than alteplase type drugs sort of like reteplase, other drugs we work with are related to plasma concentration, and that's why we give them inter-arterially. For the purposes of stroke, we need to understand that there's no,

evidence for any benefit for any treatment we have for stroke that does not improve flow to the brain, that is ischemic. We've had hundreds and hundreds of trials spending billions, and billions of dollars to find drugs that are neuroprotectant, but what we have found is that if you have dead brain, it is dead brain, and neuroprotectant drugs given after the fact, have had no effect. So therefore all efforts

these days are aimed at restoring flow as best as we can and as rapidly as we can. There's two or three different types of occlusions that we need to be aware of, for the typical heart attack, what

we have is, a conglomeration of obstructive mass that is related to a ruptured plaque. And with the ruptured plaque you have activation of platelets, and you have a resultant occlusive thrombus. And

all of these white matter areas here are platelets that are adhered to each other. The yellow strands in between are fibrin strands which tends to organize these thrombus, but the bulk of these is rapidly activated platelets due to the fact that the plaque is ruptured,

and these platelets adhere causing an occlusion. For something like this, any platelet drugs work very well, the typical sort of occlusion we get with stroke however is an organized embolus, and the embolus

is typically fibrin dominant, and so what the target is for therapy for this is, is the fibrin itself, and that's why we, give fibrinolytics which would be like alteplase, reteplase, urokinase. Platelets have a small composition of what they do, and the activation of the fibrin itself, and the activation of the fibrinolytics tend to activate platelets, and so therefore there's some sort of combination of benefit

using the two together. However in the world of stroke, we do not use typical anti-platelets with these patients, we go straight for fibrin because the main target of our therapy is the fibrin within these occlusive masses. The key thing to remember is that no drug we currently have actually dissolves clot. No lytic dissolves

clot. What dissolves clot is plasmin. Plasmin is the active agent

that actually lysis the fibrin. All lytics are just catalysts, they do nothing on their own, so all you do is you just pour more of these catalysts on top of something, they do nothing. The only thing that actually works on the fibrin strands is the plasmin itself, and that's why these things are called plasminogen activators, because they activate plasminogen into plasmin which is the active agent. Another key

factor to remember with these agents, is that the more of these agents you use is not necessarily going to be be beneficial. And an example of this is such as a car that is flooded in it's engine, more and more gas you put in there does not make the car work better, it just floods more and more and more. And we can do the same thing with clots, and occlusions

in the brain, we put more and more lytic agent in there. We go from 1 milligram a minute up to 10 up to a 100. Nothing really works faster because we cannot speed up the action of a catalyst. The catalyst is going to work the way it's supposed to work, and that is to activate plasminogen into plasmin, and then plasmin does its effect the way that it needs to. So when we say that we have clots

that are resistant to tPA they may not be really resistant, we're just not patient enough. Typically, when I'm treating an intra-arterial stroke with intra-arterial lyses, I see almost nothing for the first hour, sometimes its two hours before you see anything, and then suddenly everything starts falling apart. So plasminogen activators, the

way they work is they bind to a plasmin receptor after the plasminogen

is activated to plasmin. The plasmin binds to plasmin receptors. But so does tPA, tPA binds to plasmin receptors, and if you have all the plasmin receptors bound up by tPA, then the plasmin itself cannot get to the plasmin receptors, and therefore, it can't work. So too much tPA can possibly be counterproductive in that they

cannot get to the receptors, and therefore they cannot do the lysis that we're wanting to do. TPA itself has some interesting characteristics, one of these is that the serum half-life is very short, and the reason for this is that it immediately, goes and sticks to the clot, it was designed to be

cruise missile to go and stick to the clot just due to it's characteristics, because it is fibrin specific, and fibrin bound. The other reason is that it's cleared on first pass through the liver, and when it goes through the liver, it is removed from the serum, that's why when we use this we have to give a

bolus first to get a serum level, and then we have to give a constant infusion because it's constantly being cleared by the liver, but we still want more of this drug to get to the thrombus during the entire time. The currently used IV tPA dose used that we've got for standard

MI, and for standard stroke results in approximately 1mcg/ml

of CC, now this is an incredibly low serum level dose, but it works, and that just shows you how powerful this drug is. So if we're gonna duplicate that with an intra-aterial dose, we have to give something that is incredibly low. We've done some tests in the past, but we have done far less than we need to to understand

exactly how this process works. This is a dynamic flow model that was instructed years ago to illustrate the difference in various lytics, and how they are clot bound. There was a circulating reservoir, and blood flow would go down through this little chamber here where the clot was, and the lytic drug would go down through, and this illustrates how certain drugs are more bound to the clot than others.

But it also illustrates the speed of lysis depending on the degrees of concentration of the clot. The key thing to be aware of is if you notice that the speed gets faster, and faster. This is the time scale over here, the speed gets faster, and faster of lysis down to a certain level, and then when the concentration of the drug goes up, up, up, the speed of lysis slows down. And so therefore,

this has direct applicability to what we are doing in our field with trying to dissolve clot. Just getting in a hurry, and trying to put in more and more drug may be counterproductive for what we are trying to do. So the key thing is today, if you learn nothing else, note that Activase works worse when too much is given. Our natural tendency for most everybody including me, is that when

I'm in a hurry I wan to do more and more, and more, and hopefully speed things up, but unfortunately that's not the way this drug works. Also unfortunately, there's really been no dose ranging study for intra-arterial use of alteplase for anything, the legs or the heart or the brain. Years ago, back in the early 2000s I started a registry which was specifically designed to be a dose ranging

study for intra-arterial reteplase, and alteplase, but unfortunately we did not have enough participation to actually learn anything from this study, and to this day we still do not know the proper dose for intra-arterial use. Even in the trials that we have had including the IMS trials. We just made up numbers for how much we were going to inject, and we used that not knowing whether this was an ideal

number or not. This is an example of that previous flow model illustrating the difference between alteplase, and reteplase with the adherence

to fibrin. Notice over on this side the dark bands up here are the adherence of the drug itself to the top of the clot, and washing it really has no effect on where the drug is or where it goes. Whereas reteplase actually penetrates the clot, and gets washed

all the way through. The same thing happens with urokinase, however urokinase is no longer available. Urokinase has no clot or fibrin affinity. Urokinase is the variant of the drug that we used for stroke. Pro-urokinase is actually the pro-drug, it breaks down into urokinase, and urokinase is the effective drug that we use when we did the PPROACT study,

it has no real good use intravenously due to the fact that, that it is so non specific for fibrin. So you have to deliver it directly intra-arterially, and that's the way it was used in radiology for many years. So you have to give it directly on the thrombus, you have to infuse it continuously because it does not stick, and it does not continue to operate unless it's being given continuously.

It penetrates the clot, and therefore it might slightly a better effect due to the fact that it tends to work on all of the clot rather than just the surface. But unfortunately we do not have this drug anymore. So, what are the implications of these results, and the evidence that I've

between the use of these various agents between alteplase, and reteplase? There's been no real trial, there's been no real comparison, other than that example I just showed you. Most people have never heard of that particular paper. Because the word, rabbit was in the trial title, and a lot of radiologists don't read any papers with the word rabbit in there. And so there's no human studies of the speed of

lysis of these drugs used on actual thrombus. So unfortunately at this point, what is the best dose? How fast to give it? What is the proper dilution? We just don't know, and that's unfortunate for where we're in the world of stroke at this point. So the optimal doses for both alteplase, and reteplase at this point, at 2 fold higher or lower concentration, the previous graph showed you that the

activity was cut by about 25%. Now that's from the optimal dose, but if we're already at 100 times too much, going twice as high or twice as low might not make much difference. We also know that at about 8 fold higher or 6 fold lower concentration, that the activity was cut by 50%. But once again we don't know exactly where we are on that curve,

and I believe that the doses we are using now are tremendously too high. These examples, and studies were presented by Bookstein, and Booksteinn in an article published in 2001. From the oncology literature, we can get some understanding of the rough serum level for these drugs, and an inter-arterial infusion gives you

typically 100 to 1000 times the average dose. Now why would oncology

know this? They know this because they have chemotherapy patients, and they've got many of them, and if you give intravenous chemotherapy, they know that they have certain tremendously bad side effects. And so their aim these days is to give more, and more of these directly into the tumor bed itself. And they know that if they give these directly into the tumor bed itself, they can get between 100 and 1000 times

the tumor dose, than if you give it intravenously. They've worked this out, and they've calculated it. So if you give the same IA dose of any drug we use, you can calculate the typical IA dose by just dividing the standard IV dose by about 100 to 1000. So for stroke, if the typical dose for IV tPA is 0.9 mg/kg given in an hour. And that would be the typical dose for people

in the Unites States, then the dose that we would be aiming for intra-arterially would be 0.012 or 0.0012 mg per minute which is pretty dang low, and therefore I think we need to realize that for optimal effect, those are the ranges that we might be aiming for to get the optimal response that we are looking for, but unfortunately

I think we use far more than that. So we may be giving a hundred to a thousand times too much for the patients that we get, which would slow down lysis by how much? 90%? 99%? We don't know, but that could have direct effect on the trial that was just stopped, IMS 3 because half of the patients in that trial got intra-arterial lytic, and the trial did not have very good success. And

that's possibly related to the fact that the lysis of the clot was slowed down due to the amount of drug we were using. We just don't know, and that's unfortunate in the world we live in now. Here is something that I think is extremely important that

that is that I teach, and have taught for many years to use an

air filter on all intra-arterial lines. And that is the filter out air bubbles going into a sheath, going into a guide catheter, going into the brain, and I use it on all the microcatheters that I use to infuse drugs into the brain. Unfortunately tPA is not truly water soluble, and it gets filtered out 100% by this air filter. I've noticed in the past that it seemed like certain patients just

didn't respond to the drug as well as I expected them to. And therefore I did some testing on this, and it showed the tPA was 100% absorbed. So in the trial or IMS, I'm not sure how many people actually use those air filters, but if they did, they got lousy response on the tPA. Therefore we should not use this air filters anymore for the intra-arterial administration of tPA. This is the

poll/g air filter which has still use for every other arterial line, and I'm still looking for an air filter that would be suitable for intra-arterial use of tPA, but have not found one yet. So we need to realize that this may have had a major effect on IMS 3, but we don't know. Another interesting thing is that reteplase which is a variation of alteplase is water soluble, and it's not filtered

out. And so you can see the filter with reteplase, but it's not available in the United States at this point. However we think it's going to become available sometime in the middle of next year which would be the summer of 2013. This is how I mix alteplase for intra-arterial use. Once again, don't know the exact drug, but

thinking that I have to believe my own facts, that I've researched that I just presented to you. And that is that I mix 2 mg of alteplase, and 100ccs of normal saline, and I infuse 50 ccs per hour which would give me about 1 mg per hour through the minibore tubing. I don't use a filter anymore due to the stated reasons. I think that this

dose works just fine. It still may be high, but I don't really know. Typically we're gonna be infusing a drug into a static column of blood so it's just gonna sit there. There may be a little washing around of blood, but I think that we're getting plenty of drug to the clot that we need to, and it seems to be working when I use this concentration. Thank you, and please join me for part two

where we discuss antiplatelet agents, and other drugs useful for treatment of stroke patients during, and after the procedure. [BLANK_AUDIO]

Disclaimer: Content and materials on Medlantis are provided for educational purposes only, and are intended for use by medical professionals, not to be used self-diagnosis or self-treatment. It is not intended as, nor should it be, a substitute for independent professional medical care. Medical practitioners must make their own independent assessment before suggesting a diagnosis or recommending or instituting a course of treatment. The content and materials on Medlantis should not in any way be seen as a replacement for consultation with colleagues or other sources, or as a substitute for conventional training and study.

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