Speaker 1  00:00
Alex, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University, College of Pharmacy. We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - Dr. Abel  00:29
And now on to the show.

Dr. Sean Kane  00:31
Welcome to HelixTalk. Episode 29 I'm your co host, Dr. Kane, and I'm Dr. Patel. Today we're actually taking recommendation, a couple of recommendations that we received online. We're very passionate about receiving topic recommendations from our listeners, and we actually received a number of requests that we talk about therapeutic drug monitoring. So we've actually selected two drugs each. And Dr. Schuman is not with us today, but he'll be with us for the second segment of this, and we're going to be talking about therapeutic drug monitoring in terms of how to get a level for certain medications, what to do with that level, how to adjust it, and kind of clinical pearls and pitfalls associated with those medications.

Speaker 2  01:09
And when you think about therapeutic monitoring, few drugs come to mind right away, things like phenytoin, lithium, Warfarin is another one and a lot of controversies arise there. There are some guidelines out there by the governing bodies. However, there are some institution-specific guidelines too. So we understand how confusing it can get. Yeah.

Dr. Sean Kane  01:31
And one of the hallmarks, the reason why these medications have therapeutic drug monitoring chapters associated with them, is that they have a narrow therapeutic window, meaning that it's easy to get toxic, it's easy to have very low, poor efficacy, you know, levels with these medications. So there's a reason why they're hot topics, is that they're dangerous medications if they're not monitored appropriately. And that's what we'll be talking about today, absolutely.

Speaker 2  01:57
And I think I will go ahead and jump right out with warfarin. We know we have talked about the new or novel anticoagulants that are out there, and so Warfarin is fading. However, in certain patient population, or patients who are traditional and so used to getting their levels checked, are still using warfarin. And we've discussed in past, Warfarin is an anticoagulation. We use it to prevent clot formation in various different disease, conditions like DVT PE stroke, atrial fibrillation, they have artificial valve or even sometimes sense and the lab value be monitored to decide the therapeutic window, or therapeutic efficacy is basically INR stands for International normalized ratio. Before the discovery of international normalized ratio, we used to monitor something called PT, the proton thrombin time. The problem with monitoring PT with Warfarin was because every lab, every institution, used different reagent to find out the anticoagulant effect the time was a little bit different. So then who came in and said, No, no, we're gonna standardize this. So if a person monitors their INR in US versus Japan, it should be the same. And so basically, now we have this consistent anticoagulation effect monitoring, which is called INR.

Dr. Sean Kane  03:21
And basically, INR is a number, as you said, That's normalized using a mathematical equation that takes into account the assay specifically that's used, and basically convert that pro time, or prothrombin time, into this INR that everyone speaks the same language in terms of what an INR of 1.1 should mean as an example, exactly. Cool. So really, if you think about it, then pro time or prothrombin time, as long as you have the INR, the prothrombin time is irrelevant, because you really need to be looking at that INR instead.

Speaker 2  03:50
Absolutely, we do not need to utilize PT time for the monitoring of warfarin. And it's very funny, because sometime I call labs to obtain the levels, and that would start out, oh, the PT is this much and it's like, I really don't care about what the PT is.

Dr. Sean Kane  04:04
If anything, it can be misleading because it isn't normalized. So kind of have to report it to be able to give you the INR, or they have to at least check it. That's what an INR is made out of. But clinically, it's irrelevant, really, at this point,

Speaker 2  04:17
exactly, and two main therapeutic ranges are available, again, that depends on what indication it is. You know, if the patient was on warfarin and still had a thromboembolic event, then obviously they will monitor it a little bit higher, or they'll keep the therapeutic window a little bit higher. But the two common ones we see is level up between two and three, or 2.5 and 3.5

Dr. Sean Kane  04:40
just for reference, like a normal INR is right around one. So whether it's true or not, sometimes I tell my patients, just to give them as an example, I say, Well, my INR is one. We want your INR to be about two. So that means that you're going to be, you know, twice as anticoagulated as a normal person would be, whether it's actually twice or not, it's around. Event, but that's how the patient can kind of conceptualize an INR of two versus an INR of one in terms of how thin their blood is.

Speaker 2  05:07
Yeah, and it's very important to explain it to your patients, because sometimes they think it's the opposite, that, you know, higher means your blood is thicker because, you know, they just are going in that up direction. So it's actually the opposite. So make sure you explain it to your patient like we mentioned. It's a therapeutic window. What it means is, anything lower than this therapeutic range, patient might be at higher risk of developing a clot. Anything higher than the therapeutic range, patient might be at higher risk of developing bleeding, yeah,

Dr. Sean Kane  05:36
just to you know, emphasize some of the kinds of bleeding that we worry about. It can be anything from a fatal intracranial hemorrhage, which is a bleed in the brain. It could be spontaneous, meaning that there's no trauma, there's no structural problem. It just happened because their INR was too high. Could be something as simple as minor bruising, where they have bruises on their arms or legs because they bumped into a wall and didn't even notice it, to, you know, minor bleeding in the gums, all the way to kind of hidden bleeding, where they become anemic because they are losing small amounts of blood in their GI tract, and they don't realize it until they start becoming short of breath, and Cbc is done, and their hemoglobin is very low, and there's no source of bleeding, because it's kind of an occult bleed, where you can't really see it. There's no symptoms, aside from the anemia that you see Absolutely.

Speaker 2  06:25
And that's when we're when you're talking to patients, when the INR become available, and you're talking to them about the doses, it's really important to check all these things you know, the parameters for efficacy as well as safety that we need to assure for the patient Absolutely. And like you mentioned, Dr. Kane, we do monitor baseline INR whenever possible. Like I said, it's going to be one, but once the warfarin therapy starts, the frequency of monitoring really depends on, like I mentioned, the disease, indication, treatment, setting, whether it's outpatient versus inpatient, which we'll dive a little bit more into changes in any commitment, factors that can impact Warfarin metabolism, things like medication, diet, other disease states, so like developing an infection that can be acute or diarrhea, nausea, vomiting, and we also look at, you know, when we're talking About outpatient monitoring that time and therapeutic range, and we want to check to see how stable they are and if more the stable their INR is. We don't have to measure as frequently

Dr. Sean Kane  07:31
and just briefly speaking about time and therapeutic INR, I think this is a really fascinating topic, and the reason is that with these new or novel oral anticoagulants, when we look at the trials, they actually report this. When they look at, let's say, Dabigatran or Pradaxa versus Warfarin in the trial itself, they actually report how good the clinicians were at keeping the patient within a goal INR. And if you talk to a patient or a physician, you said, you know, where would you like, like, what percent of the time would you want to be in goal INR? I think most people would have a very high number compared to what we actually see in clinical practice. So anywhere from around 50 to 60 percentage is what we saw in those clinical trials. So almost 5050, shot of being not in therapeutic window in this relatively controlled clinical trial versus what we actually see in clinical practice is probably even lower than that, because they're not in this controlled clinical trial environment where everything is being evaluated and observed and managed and things like that, absolutely.

Speaker 2  08:29
Yeah. So I mentioned two different settings. We have the inpatient settings. Most patients, if they show up with a thrombosis in the ER or hospital, then they're going to be started on warfarin in house. And when that happens, they have the liberty and equipments to do the INRS every single day. So this is what happens, because their health status is changing so frequently in the hospital, they could be on antibiotic one day. They could be not, you know, they could have 101 degree fever one day, and the next day they could be better. And all this impacts the INR. So they'll check the INRS daily and adjust the dose accordingly. Again, nomograms are available for each institutions as to how they adjust the dose based on these INRS. But focus is going to be outpatient setting, because that's where most questions come in. Again, we mentioned the factors that would vary the range. However, the norm is that during the first week of therapy, we usually monitor it twice a week. So meaning, you know, I started somebody on warfarin on Monday, I probably will bring him back on Thursday, and then repeat again the following Monday, just to make sure that I'm not increasing the INR too fast, point two to point three units per day, is a normal or a good increase in INR. If you start seeing anything point five or above increase, then you got to cut back on the dose, because you can know it's a little too high, usually for the first month, you know clinicians will be comfortable checking this every 10. To 14 days. You know, in the first three months of therapy, anywhere again, every two to three weeks is when they would monitor and then, you know, once they become stable, once we find out what their stable doses of warfarin, we can go ahead and monitor them even monthly. So any given time I make any dose changes, I make sure that I repeat the INR in two weeks to make sure this dose is working for the patient. Obviously, you know there are drug interactions with certain antibiotics and medications like Phantom, we have amiodarone, then we want to monitor a little bit sooner, being specific about these antibiotics. Usually what I do is I if the patient tells me they are started on the antibiotic, if necessary, I'll go ahead and change the warfarin dose and then check the INR at the end of the antibiotic therapy. This is for maybe like 710 days worth of therapy of antibiotic if they're on a little longer therapy, meaning like 14 days to 21 days, I go ahead and adjust the dose first I monitor it somewhere in between the antibiotic course and at the end of antibiotic course, and then we go from there on amiodarone is a little bit tricky. Again, there are institution specific guidelines out there, from what I've been taught and what I've been doing in practice is that I monitor the INR once a week and then decrease the dose, because the drug interaction is that it can increase the INR,

Dr. Sean Kane  11:23
and that kind of makes sense too, given the half life of amiodarone is so long, it takes a really long time to get to steady state. And really steady state isn't just the amount of drug that you end up getting to. It's also related to the extent of the drug interaction that you have. So the full SIP inhibition, or the full hepatic enzyme inhibition that you see is going to be when you get to steady state. If steady state takes a long time to get there, then you're going to have to be checking your INR more frequently during that time period, because it's going to take a while for that drug interaction to fully take effect. So that makes sense.

Speaker 2  11:56
And you know, if you dive into the new guidelines that are out there, the ACCP 2012 guidelines. I was really shocked to see this recommendation, but they're saying that if your patient has consistently stable INRS, you can get away by monitoring INR every 12 weeks. We're talking about almost three months. Tell you what in the clinic, the most I've gone is eight weeks, because I have yet to encounter a patient who has consistently stable INR, we already mentioned about time and therapeutic range, it's kind of not possible. When you put it into the reality world or real world

Dr. Sean Kane  12:30
perspective, I can tell you, if I was a patient on warfarin, there's no way I would go three months without checking an INR, even if I was super rock solid, stable three months, just to me, seems way too long to wait, given how fickle Warfarin can be, how dietary changes can change your INR. There's so many different factors that I don't think that three months is something I'd be comfortable with. And you know, in talking about the frequency of INR checking, this is something I always tell patients about as soon as they get started on warfarin, or even before, when they're trying to decide between a NOAC or warfarin, the frequency of checks is a huge deal in terms of time out of your day to go to a lab to get your blood drawn or have a point of care test done. So I think setting expectations early on is really important, because what you don't want to have happen is start a patient on warfarin, and then a week or two later, they realize, oh, wow, I have to go get this checked all the time. And they really do, you know, it's pretty frequent until they get to a stable dose. And even still, it's fairly frequent that they have to be evaluated. So what about dosing? Are there any kind of clinical pearls or general concepts in terms of warfarin dosing that you see, yeah,

Speaker 2  13:41
you know, again, very specific to institutions. The ACCP 2012 guidelines have some recommendations, but rule of thumb, and this is what I've seen in practice, and what I've done is I start out with five milligrams dose. In the absence of any type of pharmacogenomic testing. We know Warfarin is affected by certain polymorphisms. We won't go a little bit deeper in that right now, some ortho units have their own guidelines. So after doing a TKA, which is the total knee replacement or total hip replacement, they'll do like a higher doses, like 7.5 for three days, and then drop it down to five milligrams every day. The need for more than 10 milligram. It's really not necessary, because we put patient at high risk of getting super therapeutic. In ours, five to seven days is when we see the pharmacodynamic effect, or the efficacy of warfarin. And, you know, and one given dose can take about two to three days to be effective. And you know, I can dive deeper into those adjustments regarding, you know, whether the INR Range is two to three, versus 2.5 3.5 again, realize that this is going to be institution specific. So if the INR is less than two, for example, you know if they they're critically. Just two to three. You have an option, if you identify any acute factors that are doing this, you can just boost the dose for one time, one dose only, and then keep the same dose and then check it in about 10 to 14 days. Or you have an option if you have identified chronic factors that are doing that, meaning you know some addition of chronic medication that will be interacting with warfarin, that will be lowering the lowering the INR, then you can increase it, increase the dose permanently by 10 to 15%

Dr. Sean Kane  15:31
let's emphasize that, because I think that this is actually fairly similar, similar to what we'll see with phenytoin, is that the dose adjustments that we make for warfarin, these are not five milligram dose adjustments. You know, if you're at five milligrams and you adjust by 10% that's half of a milligram. So these are small changes so that you're able to kind of titrate to where you want to go and not dramatically overshoot kind of where your goal doses Absolutely.

Speaker 2  15:56
And I do want to also emphasize that when I say increase by 10 to 15% this is a weekly dose and not daily dose. So make sure you calculate the weekly dose and then add 10 to 15% and then distribute as equally as possible among all the days of the week.

Dr. Sean Kane  16:12
And that's one of the reasons that that weekly average dose that you'll see patients that sometimes will take different doses on different days of the week. So maybe Monday, Wednesday, Friday, they take five milligrams, and then other days of the week they take six milligrams, and that's kind of where that comes from. It's not like Monday, Wednesday to Friday. Monday, Wednesday, Friday is a bad day for them where they need more anticoagulant. It's just how the dose comes out, because the effect of Warfarin is so long lasting that you can take the average over seven days and kind of end up with the INR that you want to be at

Speaker 2  16:42
Absolutely and we want to, we want to avoid the the peaks and valleys and the INR too. And so that's why we want to distribute that evenly as well. So if the INR is consistent, no need to change the dose. You know, keep on going. And depending on the previous stability, in INRS, measure the INR at a proper frequency. If the INR, let's say it's about five points over the therapeutic range. Again, same, like what I mentioned earlier. If it's an acute reason, you can either hold one of the doses or give maybe half the dose that day off. And the reason behind half the dose is actually for patients who are on higher doses. So for example, I have a patient taking two milligrams every day, their INR came up to be 3.4 I can go ahead and tell him, Hey, let's skip the dose today and then continue the two milligrams every day. I have a patient who's taking 10 milligrams every day, and their INR is 3.4 if I ask them to drop that 10 milligram the entire dose that day, their INR is going to drop pretty fast. So higher than the dose daily dose, the higher the drop would be if you omit that dose. So what I do in that case, I say, Let's do five milligram today instead. Or depending on your judgment, you can even do 2.5 milligram. If the changes patients have made, or there are are chronic you can again increase the weekly dose by 10 to 15% in this case, again, if you see the INR higher than therapeutic range, I would say maybe up to a whole point or whole unit higher, then you have an option. Again, if it's an acute issue, you can hold one to two doses. Or if it's a chronic issue, you can actually decrease the dose by, again, 15 to 20% if the INR, let's say, is greater than four and the therapeutic range is 2.0 or 3.0 or 4.5 where their therapeutic range is 2.5 or 3.5 again, holding one to two doses and decreasing the dose by 15 to 20% because the INR is little bit higher than the therapeutic range it should be. And then, you know, beyond this, you get into issues where they call super therapy, Supra therapeutic INR management, again, institution specific guidelines are out there. What I do in the clinic, if I see any INRS between five and 10 and patient has not complained of any bleeding. I go through all my checklist and bleeding points, then I usually ask them to hold the warfarin for three days, come to the lab, get their INR checked, and then maybe start at a lower dose. A lot of the times I've seen either patients have taken wrong dose. That's the reason behind this increase in INR. Sometimes patient took amiodarone, didn't forgot to tell you that they started on amiodarone or antibiotics some sort of reversible reason. So if that is the case, then you can actually start at the same dose after correcting it by holding it for two to three days. But if that's not the reason, then we should probably start the lower dose, 15 to 20% lower dose. Again, if the INR is greater than 10 and yet no bleeding, the recommendation come directly from the ACCP 2012 guidelines, again, holding the warfarin giving about 2.5 to five milligrams of. Oral vitamin K and then rechecking their INR in three days, and maybe starting at a lower dose.

Dr. Sean Kane  20:05
Now, if a patient who's taking warfarin does have bleeding regardless of their INR, then certain measures have to be taken in order to reverse their coagulopathy. So this could involve things like Vitamin K. Could involve blood products like fresh frozen plasma. There's even new products on the market called PCCs, or prothrombin complex concentrates. Right now, the most common one approved by the FDA is called kcentra. The dosing and usage of these various agents is kind of beyond the scope of today's podcast, but suffice it to say that most institutions will have some kind of a protocol in terms of when to select various agents and what the follow up of those antidotes, if you will, should be for different types of bleeding for patients who are taking warfarin.

Speaker 2  20:51
So switching gears a little bit, I'm going to give the microphone to Dr. Kane and talk about how we deal with therapeutic window when it comes to phenotype. So in

Dr. Sean Kane  21:01
terms of phenytoin, just some basic background, phenytoin, or Dilantin, is the brand name. So this is an anti epileptic that's primarily used for two different kinds of seizures. So one kind is a generalized tonic clonic, or some sometimes people refer to it as a grand mal seizure, and then the other type is a partial seizure. And really the distinction between the two is whether it involves the entire brain or just part of the brain, the way that phenotype works is two different ways. One way is that it blocks sodium channels, so it basically makes it more difficult for your brain to fire along a pathway. And the way that seizures work is that they kind of have this uncontrolled firing. So if we slow down and inhibit the brain's ability to fire, that's how phenytoin works. It also promotes GABA activity. So we see GABA with things like benzodiazepines, where they promote GABA activity. Typically, this GABA activity is only at higher doses, but it also contributes a lot to the adverse effect profile that we see with phenytoin at higher drug levels. So whenever I think of GABA, I always think of alcohol. Intoxication with alcohol is very similar to intoxication, at least within a certain point with phenytoin, in the sense that you'll see patients who exhibit similar signs and symptoms of being drunk when they have high phenytoin levels.

Speaker 2  22:13
And so this probably leads into why we need to monitor phenytoin

Dr. Sean Kane  22:18
levels exactly so we have a narrow therapeutic window, in the sense that at higher levels, we see unacceptable adverse effects. So, you know, inhibit quality of life for these patients. So we can't have really, really high drug levels. And then also, kinetically, there's some things with phenotype that make it really unique.

Speaker 2  22:36
And that reminds me, you know, when I was a student, why I couldn't wrap my head around how to, you know, understand the the pkpd of phenotype in how to monitor patients. So what are those distinguished pharmacokinetic issues with phenotype?

Dr. Sean Kane  22:50
Yeah, so two of the more basic things with it. One is that it's protein bound, and the thing, the part of the molecule that's found in the protein, doesn't do anything. It just kind of hangs out there. The part that isn't bound the free fraction, or the free portion, or the unbound amount of phenytoin. That's the stuff that has the magic of crossing the blood brain barrier, getting into your central nervous system and exhibiting both the efficacy and the safety effects that you'll see. So protein binding is bad, in the sense that drugs can compete for these protein binding sites. So valproic acid, which is another anti epileptic, is well known for competing with phenytoin for this protein binding site. If it competes, it kicks it off, and you end up with more free phenytoin, which more of it will cross the blood brain barrier and you'll get more of an effect, even if you still have the same amount of phenytoin. So that's one thing. The second thing is that it will induce hepatic metabolism, meaning that when you take phenytoin, and let's say you're on warfarin, at the same time, the warfarin will be metabolized off quicker, meaning that your INR will drop because you have more hepatic enzymes that are chewing up the warfarin. But that also means that phenytoin does go through the liver to be metabolized, so it's susceptible to hepatic drug interaction. So amiodarone, for example, amiodarone is a SIP inhibitor. It will inhibit the metabolism of phenytoin, which means that your phenytoin levels will go up. So both of those are fairly standard in terms of we see that kind of a drug interaction and those kinetic parameters with many other drugs. The really unique thing with phenytoin, though, is what's called Michaelis Menten kinetics, or saturable metabolism. What that means is that when a patient takes phenytoin, at one point, if you increase the phenytoin level by 50% your drug level will increase by 50% but at some point, this is within the therapeutic range of where we typically dose phenytoin, at some point you'll hit this saturation point, where, as you start increasing your drug dose, your level dramatically increases way more than the amount that you increase the dose by. This is called saturable metabolism, which just means that the liver isn't able to keep up with metabolizing off the drug, and you end up. With really, really high levels very quickly when you just increase the dose by just a small amount. So as you mentioned, Dr. Patel, this is why we have therapeutic, direct monitoring of phenytoin. So kinetically, it has three things that make it unpredictable, something that we need to monitor, and we see toxicity with it. So as we start increasing our dose and increasing our levels, we see nystagmus, which is where the pupil will bounce when you're looking in the periphery. This is what you'll see when a police officer is giving a driver a DUI test. They hold their finger in front of the driver's nose, and then they move it to the periphery to see how much the eye the pupil bounces. And that's called nystagmus. So you'll see that with phenytoin, as we get to higher levels, as the levels get even higher, you'll see sort of speech. You'll see in coordination. Remember, these are some of the GABAergic effects that are that we see with all GABA activity, including alcohol. At some point when we get to very high level, so 40 to 50 range, you're going to see confusion, lethargy, coma, and then it seems odd, but you can even see drug induced seizures, even though it's an anti epileptic at very high doses. And eventually patients can die from phenotype toxicity. So this is something that it's really important that we follow drug levels and understand what modifies the drug level. And, you know, watch out for those things

Speaker 2  26:20
absolutely and, you know, I don't encounter phenytoin as often in my practice, because I'm in a family practice clinic. However, I do see patients being on phenytoin and kind of messing up my INR levels when they're on warfarin. I do not like that. But I did actually encounter a patient whose phenytoin level was checked over the weekend and was not addressed, and it was obviously high phenytoin level. Upon calling the patient, found out that she had the first two of the toxicity, nystagmus, as well as slurred speech and confusion out of the four that you just mentioned. And I had to pick up the call, and I didn't want to change any dosing at the point because a neurologist was seeing her, but we ended up admitting the patient in the hospital and observing the patient and, you know, basically cutting off the phenytoin at

Dr. Sean Kane  27:11
that point. Well, think about how important patient counseling is for that patient, or any patient really, who's on phenytoin is if they can recognize some of the signs and symptoms of toxicity, in terms of, you know, in coordination, slurred speech, things like that. They themselves are kind of a barometer for whether their level is high or not. They're going to know better than anyone in terms of, you know, hey, it's time to get a phenotype level check, because I don't feel right, or I'm having some of these symptoms that are not normal for me. So to counsel a patient to be able to do that, make the phone call to the provider and get a Level Check. That's really, really important to avoid that level getting even worse over a day or two. You know that that needs to be monitored.

Speaker 2  27:52
Yeah, and with all those things you just mentioned, plus the PK parameter, you know that are very specific to phenotype, and let's talk about the level. When do we measure them, and what do they actually mean when the dose changes?

Dr. Sean Kane  28:06
Happening? Yeah, definitely. So on the outpatient setting, ideally you want to get a trough level. So you want to get a level before the patient takes their dose. On the inpatient side, especially, this can become more relevant. It's okay to have a random level. What that means is that if someone just had a seizure, and we want to know what is their phenytoin level right now, it doesn't matter to us when their last dose was. We're going to get a random level to just see where they're at. And if their level is extremely low, we're going to give them a lot of phenytoin to kind of load them up, whereas if their level is already high, even though it's a random level, we're not going to give them more phenytoin, because this random level is high. So the random level, the point of that is to say, hey, I need to give more phenytoin or not. The trough level is to ascertain whether you should be adjusting a maintenance dose or not. So when you actually get a level, when you order it, there's kind of two flavors of phenytoin levels. One is a total phenytoin, which basically tells you all of the phenytoin amount that is in the blood sample you drew. So it's

Speaker 2  29:03
So basically what's attached to the protein and what's free exactly

Dr. Sean Kane  29:08
in the blood Exactly. So you get the bound and unbound altogether, and you can't distinguish the two. The other way that we can do it is kind of a newer assay called the free phenytoin level. When we say free, we mean unbound. So the amount of phenytoin that isn't bound is biologically active. The stuff that crosses that blood brain barrier that inhibits the sodium channels and the GABA is GABAergic. That's the thing that we actually care about. For historical reasons, though, it was easier to get a total level rather than a free level. So at many institutions, you either can't get a free level. Or if you do send for a free level, it takes a day or even longer to kind of get that level back. So for convenience and kind of logistics, sometimes you're forced to get this total level, which isn't as good, whereas you'd like to get a free level if you could

Speaker 2  29:55
absolutely and in patients who have maybe low albumin level. Because of the nutrition and stuff. Would you say? Then the free levels are more important, because we want to check how much free phenotype is there. Absolutely.

Dr. Sean Kane  30:08
So anytime you see a total phenotype level, if it's a sick patient where they have a low albumin, that total phenytoin level is lying to you, you have to correct for it. There's correction equations out there, the most common one is called the winter Tozer equation. There's actually been a number of iterations of that equation that have been published. But the point being is that when you see that total level, if their albumin is less than four grams per deciliter, you have to correct for it, because you're not accounting for an increased amount of the free fraction of the phenytoin in the blood. So in terms of goals, either correct at phenytoin level or a true total phenytoin level, we want that to be between 10 and 20, knowing that some patients will have an anti seizure effect lower than 10, and some patients will have unacceptable toxicities within that 10 to 20 range. So this is a general guideline. It's not a black and white issue. With that. Said the free level is about 10% of that. So it turns out that 10% of phenytoin is free, whereas 90% is protein bound. So our free phenytoin level, our goal is one to two, which is 10% of 10 to 20.

Speaker 2  31:14
That makes sense. And you know, I've maybe jumped the gun and talked about the low albumin. But what other factors can impact the total phenotype levels, and can give us the misrepresentation of the level. Yeah.

Dr. Sean Kane  31:27
So one thing is they have to be at steady state if you're going to interpret that to adjust their maintenance dose. So the half life of phenotype, because it has a saturable metabolism, the half life can actually vary. So sometimes the half life can be very, very short at lower drug levels, but if you are near or above the saturation point, your half life can actually be fairly long. So as a typical rule of thumb, we'll say that steady state is between seven and 14 days, meaning that a typical half life is going to be just longer than a day, but it could be as long as two days, depending on the patient. So that's point number one is gotta be at steady state. Point number two is that if you do have that low albumin level, you really need to be correcting, doing a corrected total phenytoin or just getting a free phenytoin level and not worrying about the albumin. There's two other patient populations that can really throw a monkey wrench in your total phenytoin level. One is patients who have end stage renal disease, or uremic patients. The reason is that uremic toxins can compete with the protein binding site of phenytoin, so you end up with your free and total phenytoin levels being discordant, meaning that you end up having a lot more free phenytoin that you expect you should have. And for that reason, there is another correction equation for that, but it's not well proven out in the literature, and I'd be very cautious about using that. The other patient population are patients who are on other protein bound drugs that could also compete for the protein binding site. The most common is going to be valproic acid, and there, again, are correction equations for that. But again, I'd still be fairly cautious if you can reliably get a free phenotype level, and patients who have very low albumin are uremic patients or valproic acid concurrent patients, it's really the best approach is to get a free level if you can get it in a reasonable amount of time. So in terms of dose adjustments, just like warfarin, this is more art than science. There are some published nomograms and recommendations in terms of how to adjust. But as a general rule of thumb, if your phenotype level is low, and you verified it's either a total correct at phenytoin level or an actual free phenotype level, and you know it's low, you have two things that you need to think about. One is, is it low enough that you're worried about the patient having a seizure, and if they you are worried, then you probably should give them a loading dose to make sure that they don't have a seizure in the you know, day to two days that it's going to take for them to get to a therapeutic level. So there's two ways that you can give a loading dose. One is you can actually give an oral loading dose. And this is actually kind of a faux pas, in the sense that many clinicians are not comfortable giving oral phenytoin loading doses, but there's actually good data that says that you can get away with it, and it's okay. The caveat to that is that it takes a while to actually get the peak level. So unlike many oral drugs with phenytoin, has a saturable absorption process. So when you give a full loading dose of oral phenytoin, it can take up to 12 hours for the entire peak effect to take place, which 12 hours is kind of a long time if you think about a patient who's at high risk for having a seizure. So for those patients, we can give IV phenytoin, but most hospitals don't carry IV phenytoin anymore because it is a vesicant. It can cause tissue damage if it extravagates Out of the IV line, and there's some other issues

Speaker 2  34:45
with it. So let me guess they use fosphenytoin,

Dr. Sean Kane  34:48
exactly so fast. Phenytoin is a chemically modified phenytoin where it's more water soluble. We don't have to package it in a very, very high pH solution. Basically, we'll be. Be cleaved off in the liver into phenytoin. So you end up getting phenytoin. It just has to go through this biotransformation process. So it's a pro drug. So we can give that IV as a bolus dose to get the patient up to a therapeutic level, if we're very concerned about them having a seizure, or maybe they just had a seizure, and we want to get them to a therapeutic level as soon as possible.

Speaker 2  35:19
And then what about, you know, they're not at an imminent risk of developing seizure, meaning they don't need a loading dose. We just want to, you know, routinely update their maintenance dose. What do we do?

Dr. Sean Kane  35:30
Yeah, so just like with warfarin, slow, small changes is really what we're going after with phenytoin. So to give you an example, a typical phenytoin dose is about 100 milligrams three times a day. So 300 milligrams a day, a typical adjustment is going to be somewhere between 3050, maybe 60 milligrams at the most per day. So these are fairly small adjustments. Obviously, every patient is different. It depends on the clinical picture, but generally speaking, you're making extremely small adjustments to the daily dose, and the reason being that if you make too large of an adjustment, you end up over shooting. You end up in the saturable metabolism area where the patient's level goes from eight to 42 and you've really messed up so small and steady wins the race with phenytoin, just like with warfarin. In terms of if you have a high dose, things get a lot more complicated. Generally, we don't have good evidence of nomograms in terms of what to do if you have a high phenotype level. It's fairly similar to what we discussed with warfarin, where you'll probably hold one maybe two doses. If it's very high, you may hold a number of doses and get a repeat level. It depends if you're in the hospital or not, how easy it is to get a new level. Generally, though, you're making small downward adjustments, just like with upward adjustments, and obviously it depends on how high it is, but generally, you're trying to make small adjustments so that the patient doesn't end up having a seizure because you over adjust it. So we're just as worried about safety as we are with efficacy, and it goes both ways. In terms of the smaller the adjustment you make, the better you are at being able to titrate that patient. And keep in mind, it takes seven to 14 days to get to steady state, so when you make that adjustment, you won't know the net effect for seven to 14 days when you get a new level, when they're at their new steady state.

Speaker 2  37:13
So you're saying, if we make these adjustments in the maintenance dose, we should be asking patients to come back within seven to 14 days to see if this new dose is working out

Dr. Sean Kane  37:23
for an MRI, absolutely. And again, every patient is going to be different in terms of what's going on with them. So in the hospital setting, we might check for the tone levels every day, or every couple days. If they just had a seizure, we're going to be more adamant about getting frequent levels. Or if we send them home and say, we'll check it in seven to 14 days. And on day three, they say, Hey, I'm having difficulty walking, and I keep falling over. It's probably time to get a phenytoin level checked, because they're exhibiting signs and symptoms of toxicity. So a rule of thumb is seven to 14 days, but clearly earlier if they have a seizure or if they are having toxicity signs and symptoms, just like with any other drug. Okay, so with that, we're going to go ahead and conclude this portion of today's episode. We're going to be resuming with the next episode. Dr. Schumann, hopefully will be able to attend, and we'll be able to pick his brain about one of his two drugs. This is going to be a continuing series for six total drugs, and we think that this is a really important topic, because pharmacists play a very important role in therapeutic drug monitoring, making recommendations regarding when to check levels, what to do with the level, how to interpret the level, what to do with the dosing based on the level. So there's a lot of content here, and the reason it's so important is that these have very narrow therapeutic windows, and we want to make sure that we're avoiding some of the adverse effects, but promoting the efficacy of the medication.

Speaker 2  38:42
And trust me, you know being in the family practice or, you know, an outpatient care setting, I do know that clinicians usually turn to you when such cases arise. So having this knowledge is very pertinent, absolutely.

Dr. Sean Kane  38:56
So if you haven't done so already, we would really appreciate a five star review on iTunes. We're available by searching for HelixTalk, and we're also available at HelixTalk.com if you have any episode suggestions or topics that you want to hear about, just like today's episode, you can email us, and our email address is available at HelixTalk.com With that, I'll go ahead and sign off.

Unknown Speaker  39:15
I'm Dr. Kaneand I'm Dr. Patel, and as always, study hard.

Narrator - Dr. Abel  39:19
Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science. For more information about the show, please visit us at HelixTalk.com you.