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. And now Narrator - Dr. Abel 00:29 on to the show. Welcome Dr. Sean Kane 00:32 to Episode 31 of HelixTalk. I'm your co host, Dr. Kane. I'm Dr. Schuman, and I'm Dr. Patel, and today we have the dream team back. Dr. Patel was gone on vacation. Congratulations again on your wedding and honeymoon. Thank you and Dr. Schuman, we spoke last episode, but it's good to have you back from Speaker 2 00:49 Honduras, yep. Ready again, ready to get back the three of us in that kind of consistency for a few weeks, to get really nailing down some good subjects again. Unknown Speaker 00:57 I too, am excited. Great. Dr. Sean Kane 00:59 So today's episode, we're going to kind of finalize what we've been talking about the last two episodes, which is therapeutic drug monitoring of kind of clinically relevant, common medications that pharmacists play an important role in. So just to recap, the first episode, we talked about phenytoin or Dilantin and warfarin or Coumadin. The second episode, we talked about valproic acid, Depakote, depakine, depakon, and digoxin, or lanoxin. And today we're talking about with Dr. Patel, oral tacrolimus, and with Dr. Schuman, we're going to be talking about lithium. So Dr. Patel, would you like to kind of kick us off with your drug of choice today? Speaker 3 01:37 Sure thing. So we're going to be talking about, how do we monitor and what goes with the whole oral tacrolimus therapy. Brand name is Prograf, as we all know, it's an immunosuppressant, and in particular, it's a calcineurin inhibitor, which is used as an anti-rejection agent, along with some other agents too in various different transplant patients. So basically the mechanism of action is dampening down the T cell activity by binding to the intracellular protein complex, which is the FKBP12, and then making further complexes with the calcineurin dependent proteins to basically reduce the calcineurin phosphatase activity, which is responsible for T cell activation. So we are trying to basically inhibit the T cell activation here. I assume Dr. Sean Kane 02:25 when you say transplant patients, you mean solid organ transplant patients. Speaker 3 02:29 That is correct. Okay, yeah, I should like to make that clarification here. This is not for bone marrow transplant. It's for a solid organ transplant. Cool. Okay. And so when it comes to monitoring, you know, if you're working currently, you see that FK506 level. Sometimes the lab reports it as FK506 level monitoring, or sometimes it will say, tacrolimus level. It means the same thing. Then, right? It means the same thing. Yeah. So if you're looking into your budget lab section in the patient chart, you know, 506 versus tacro, it's the same thing. Good thing that we get some sort of level. Bad thing is that there is no real correlation between what this level comes back to, as to what dose has been given to the patient or how much drug is actually in the blood. So sometimes this variability comes from a couple different factors which affect the drug's absorption and metabolism. The ultimate things that affect the absorption and metabolism is, you know, whether patients are taking this medication with food or not, right? First thing that comes with absorption in mind is food. Second thing is, if there are changes in the P-glycoprotein, which are located in the gut area, the absorption of this drug is also affected, as well as some metabolism too. And then if patients have additional hepatic impairment, the response to this drug will be different. So basically, if there is a noted hepatic impairment, there is about threefold increase in tacrolimus half-life, and sometimes that can correlate to about 30% decrease in clearance of this drug from the body. Dr. Sean Kane 04:04 So clearly, it's a hepatically eliminated or metabolized drug. Then right? That is correct? Got it, and I can tell you that at least on the inpatient side, I know that people who are involved in solid organ transplant are very religious about making sure that this is given exactly at the right time of day. So I've been at institutions where it's always 6am 6pm because lab draws are 5:30am and that way they can ensure that they get a true trough level at the same time. It's always given at the same time. And because of the variability with timing and food and things like that, it makes sense that you'd be so concerned about making sure that your level is as consistent as you can possibly make it Speaker 3 04:42 absolutely so you got it. We do monitor the trough levels, and like I said, in most institutionalized patients as well as patients who are at home, especially when they're discharged at home and they're on that initial dose, which can warrant further titration, we want to train patients to take the doses, preferably at the same time every day, so like 7am 7pm so they can come and report to the lab at around six o'clock or 6:30 to check this trough level. Trough level, we can extrapolate to how much toxicity, or what type of toxicity they would have, but there is no real correlation with how much efficacy there is looking at these trough levels. So again, we will talk about different goals of FK506 levels for different types of organ transplant patients. But let's talk about what happens when the drug level is too high. So talk about different toxicities. Okay, the main two toxicities that come in the picture are nephrotoxicity and neurotoxicity. In some patients, they have seen increased blood pressure or heart rate, some nausea and vomiting. Although this nausea, vomiting is not as apparent as digoxin toxicity, as you might have heard during the last episode, hyperkalemia is one of these toxicities as well and as part of the neurotoxicity, some patients may present with seizures, blurred vision, and sometimes, because of that inactivation of or inhibition of T cell activation, you might put patient at high risk of infection. And this is actually a box warning for this agent itself. So these were the issues. If the level is too high, that means, conversely, if the level is too low, we are looking at possibility of organ rejection, and the signs of organ rejection would be basically tissue damage to the organ that is transplanted, basically your body, then host cell will start attacking the new organ that's transplanted. Great. Dr. Sean Kane 06:35 So in terms of thinking about the level, I understand that too high, we get, obviously, toxicities, primarily neuronephro toxicity, too low, we lose the organ that was transplanted. What are some of the nuances of actually obtaining that level in terms of clinical pearls, if you will? Right? Speaker 3 06:52 So one, I think we already mentioned, so if the patients are taking this BID regimen at home, we make sure that they take it at a particular time and remain that make that time consistent. So usually we schedule patient to take this BID dose, 8am 8pm so we can check their levels at around, you know, six or seven o'clock in the morning, that will be the true trough level. We usually monitor this level more frequently in the beginning of the therapy, while we are titrating the dose, because, again, every organ transplant patient has different goals of the tacro level, and so we are basically trying to find out what regimen works best for this patient. Dr. Sean Kane 07:29 And I haven't seen a lot of liver transplant patients, but given the drug is metabolized in the liver, I would imagine that a liver transplant patient on day one of their transplant will probably metabolize differently than day 30 of their transplant. Unknown Speaker 07:42 That is correct, absolutely correct. Now, Speaker 2 07:45 are there any drug drug interactions that can contribute to these levels being altered? I assume that many other medications that may have potential for hepatotoxicity could impair this drug's metabolism correct. Speaker 3 07:56 So I think the ones that actually impact the P-glycoprotein are the drugs that would usually interact with tacrolimus. And we know we have a long list of the P-glycoprotein interacting drugs too. Dr. Sean Kane 08:06 We talked about it in the last episode with digoxin, with amiodarone being a dramatic player in a drug interaction between digoxin and amiodarone. Speaker 3 08:16 Yeah. Again, that mechanism is also P-glycoprotein mechanism. The tacrolimus levels, again, is also used whenever you're trying to change your dose. So you're let's say, for transplant patient, they are probably managed on more than one anti-rejection medication. So if they're trying to add another medication on board, then you might have to adjust the dose of the tacrolimus, and at that point, you also want to check the level again to make sure that patients are in the right therapeutic window, and again, if they're noticing any signs of toxicity, all the things that we mentioned again, neurotoxicity, nephrotoxicity, or increased blood pressure, heart rate, things like that. So without going in detail about the reference range, because there are very many different reference ranges for different organ transplants, just in general, these ranges depend on also the concomitant transplant medication and then also the risk of rejection or ischemic injury to that particular patient. So in a normal setting, your transplant team, whether it be inpatient or outpatient, would be the one deciding what patient would go home with but usually give you an example. Kidney transplant is the most commonly done transplant, and patients who are using this with azathioprine for the month one until three, we are looking at the tacro level to be between seven to 12 nanogram per milliliter. And then month four to 12, you're looking at five to 15 nanogram per milliliter. Same thing if they're using mycophenolate or daclizumab, those are other anti-rejection medications in patients with kidney transplant. From month one until 12, you're using that level to be four until 11 Dr. Sean Kane 09:58 nanogram per milliliter. Okay, so I guess take home points in terms of goal ranges. For the trough is a, it's a trough. A typical range is somewhere between five to 15, five to 20, and it's really based on the transplant team. It's not like something you just look up and say, Oh, you're probably a level of blank, because it really depends on all of the other rejection meds that they're on then Speaker 3 10:21 absolutely so if you are not. You know a pharmacist who's not involved with the transplant team, but happen to see an FK506 level to be, let's say, 35 it would be a good idea to maybe bring that up to attention to the primary care provider or even the transplant team, if they haven't looked up the results yet, because at that point, patient might have some sort of toxicity. As we said, the most common range is five to 20. And then it really depends on where the team wants to manage the patient at. Dr. Sean Kane 10:50 And I can tell you, in my ICU, we don't receive new transplant patients, but we may get a transplant patient who got a transplant three years ago and is now in our ICU for a completely unrelated thing. Let's say they have an infection and now have septic shock. On every single one of those patients, we're always in contact and communication with the original transplant team, whoever follows them up, because this is such a patient specific thing, and the consequences of messing it up by not giving them their tacrolimus back when you need to, not following levels appropriately, and it being too low or too high, those consequences could be organ failure of whatever transplanted organ they had. That's a really big deal. So you're always holding hands with whoever the transplant team is to make sure that you're you're providing the appropriate care for the patient, absolutely. Speaker 3 11:39 And I think this point is driven to patients' brains pretty seriously by the transplant team, because I have interacted with a few patients in my anticoag clinic who have transplanted organs. And, you know, any type of changes in medication, they always tell me, Oh, I always communicate to my transplant team, or I'm going to call Dr. so and so he's my transplant doctor. So yes, this is a great example of communication, good communication in the medical Dr. Sean Kane 12:06 environment, which is actually, to me, a little bit comforting as well, because it means that I shouldn't be the one modifying the tacrolimus dose based on a level. As an example, it should be in conjunction with the team, so I don't need to know the nuances of adjusting to Chrome this dose, because I really should be communicating that with the team in the first place, Speaker 2 12:26 absolutely right. But at the same time, you know, it is nice to have a little bit of information, as we said, so you can raise the alarm. Should you see something that is grossly elevated? Exactly. Dr. Sean Kane 12:35 Yep. All right. Well, Dr. Schuman, why don't we move on to lithium? I imagine this is well within your wheelhouse of expertise. Speaker 2 12:43 Sure, this is a, you know, it's a medication that has been around for many, many years, and despite a whole lot of other medications coming onto the market, atypical antipsychotics, for example, that there still is a huge role for this medication. Now it's used primarily in the treatment of bipolar disorder, both acute and maintenance treatment, where it still is one of the, the most reliable medications that we can go to. And then it's also used in patients with severe treatment resistant depression. It's down there furthered on past once you get our SSRIs or SNRIs, and then also for individuals that do have suicidal behavior, there's some some evidence that lithium may have benefit in that population Dr. Sean Kane 13:21 particularly so I don't want to get too much into the treatment of bipolar disorder. Maybe it's something we could talk about in the future. But is it normal, then, for a patient to be on valproic acid and lithium at the same time, you know, a drug that we talked about in the last episode, or is it usually one or the other? What is a typical regimen that someone might expect a patient to Speaker 2 13:40 be on most of the time it's released. Initially, you're going to start with one agent or the other, but you will sometimes see that combination being used for somebody who does continue to have resistant symptoms, or if somebody had aggression, or even if we're treating migraines. There's other reasons you may still see that combination, since lithium, which doesn't have that migraine indication, not generally. So we still may see the combo. And since you mentioned Depakote or about procastin, one of things we'll get to later is that there's a big difference in terms of standard, of how they get a level, or how important it is. I'll get to that in a little bit. The one thing is that this is a medication that comes in three salt forms. There's lithium carbonate and lithium citrate, are the two that are FDA approved. And then lithium carbonate, the first one comes in immediate release capsule, immediate release tablet, and then an extended release tablet, and then lithium citrate only comes in immediate release syrup. And then there's lithium orotate. And I want to just real quickly bring, bring that one up, since it's interesting. This is available as an OTC supplement, one that, believe it or not, you can just go on amazon.com and order right now. Dr. Sean Kane 14:43 Interesting. So you're saying not approved by the FDA, but pretty much has the same active ingredient. It's just a different salt form, Speaker 2 14:51 and that's the thing. It's been touted as a safer alternative. Do some they could. There's the claim that it has an enhanced bioavailability, and if you read some of the you. Amazon reviews on they're somewhat surprising. It's one says, quote, it's an inexpensive, easy to take over the counter supplement with no side effects. And now that's, that's the the part that I I'm going to kind of leave you with, and that's, that's what the importance of, kind of clarifying these things. Just because it is available, just because somebody reviews, it doesn't necessarily mean it's appropriate, because this one Speaker 3 15:19 doesn't really have any data. So we mentioned different salt forms. Let's say, you know, an out practitioner wants to change from one salt form to another salt form. Do we have to be aware of different bioavailabilities, or are they pretty much same across Speaker 2 15:32 the board, bioavailability is going to be the same between these two, essentially, very similar. But the one thing that will come into play, and we'll talk about the half life zone in terms of getting the levels. So as I said, just want to be careful about using these other kind of ones to orotate. So now we just move on to the real ones. You'll see in practice is going to be lithium itself as a citrate or carbonate, and this is a medication that does have a very narrow therapeutic window, much more narrow than with valproic acid. We have a range of point six to 1.2 and that's the goal, and that's the trough concentration for most situations. And then in severely acute individuals, again, very severe mania or very severe suicidality associated with it, agitation, you can consider 1.2 to 1.5 and as always, it's going to be a risk benefit. And the therapeutic ranges are based upon a steady state concentration, and we get that about 12 hours after the last dose of medication. And so C max is about or max concentration is about 15 to 30 minutes after the syrup, one to three hours after immediate release, and four to eight hours after the extended release tablet. And then what's interesting is, similarly, we talk about some of the unusual kinetics with Dr. King, with some of your medications that you discussed, this is when you really see a sharp drop over six to 10 hours after you administer it. And so you really want to wait until after that point to get that true trough level. And that's why we usually see it about 12 hours after dosing. So once we've given doses to four to five doses to get to somebody at steady state, and then we wait until 12 hours after the last dose to get that trough, because we need to wait for that full six to 10 hours, plus the amount of time you add in, then the amount of time for the initial absorption, or 2c max. So that gets us Dr. Sean Kane 17:18 about 12 hours. So Dr. Schuman, how often are we dosing these different dosage forms for a typical patient? Speaker 2 17:24 And again, that's going to depend upon the kind of the formulation we're using. The immediate release formulation of lithium needs to be given about three times a day, really, to see a good, consistent, steady state level. You can do less frequent dosing. You may see for some individuals that have compliance issues, or if there's concerns about side effects like somnolence, you may give it 900 milligrams at bedtime. But the problem with fat is that you're going to see a really low trough level. And so if you saw low trough level, what would you do? Increase the dose, right? And then what happens now is we're going to get a higher peak, and then we're going to have a little bit higher risk of those side effects. So most of the time, the better option to use is an extended release product, so that the C max, or the peak there is going to be more approximate to the trough level. And so we know that we're not going to see these gross increases. So if we have a trough that's within range, we're probably not going to see somebody deviating so far in their peak that they're going Dr. Sean Kane 18:21 to be having these side effects. And the extended release product, is that a once daily product, or how often is it typically? Speaker 2 18:27 And that's one the control release still, you really need to give twice a day to be able to really monitor again. It's very often given once a day. But if you really, really want to be sure that that when you adjust the trough level, that you're not completely making them shoot up at the other times of the day. You really want to be giving it at that zero and 12 hour range. Dr. Sean Kane 18:47 So it's kind of nice then, because, as we talked about with digoxin, you have to wait at least 12 hours for the same reason, this kind of delayed distribution phase. But in this case, if you're typically dosing it twice a day, unlike digoxin, you're really getting both kind of two birds with one stone. You're waiting 12 hours and you're actually getting a trough if you dose it twice a day, then by getting a 12 hour level. So effectively, you're getting a trough if they get it twice a day. This is that you can't get it any earlier than a 12 hour period Speaker 2 19:15 right now. It's the important thing. And again, you have to let patient compliance be a factor, and then just be aware that if you are doing one of the different dosing regimen, you just have to keep that in the back of your mind. And the other thing about lithium is that if you look at it on the periodic table as a monovalent cation, it's in the same column with sodium. They're very similar on a molecular level, and so the kidneys, a lot of times, have difficulty distinguishing them from another. And so there's some similar transport mechanisms, which means a lot of the interactions with this medication is very sensitive to drug interactions. A lot of them have to do with the kidneys and sodium excretion. So if you think about medications like your NSAIDs, with generally thought, the exception of solid act, but NSAIDs, the. Hydration, vomiting, diarrhea, age, and with age coming decreased renal function. You see an increase in lithium concentrations. Dr. Sean Kane 20:08 So when you say thiazide diuretics, we're talking hydrochlorothiazide, chlorthalidone, probably the big two players that you're commonly see in practice in Right, right? Speaker 2 20:17 It's really interesting when, when you lead to hyponatremia or sodim excretions increase in the proximal tubule, you see an increase in lithium to compensate. So loop diuretics don't really do anything. Thiazide diuretics crank up your lithium level, and then caffeine is generally thought to tank the lithium levels. So this is something that can be very important when you have an individual that presents and they're decompensating. You can look at medications that have changed, individuals that have decided to go from no coffee to a lot more coffee. And you can see these fluctuations in individuals who then end up with a sub therapeutic lifting level and then are presented to the hospital with a humanic Dr. Sean Kane 20:51 episode when you say, caffeine. Is it like a cup of coffee? Or do they have to have a pretty appreciable amount for it? Speaker 2 20:57 Generally appreciable. When I think of a couple of the individuals, I'm thinking of multiple cops or leaders, of one individual that decided that it's going to go back to his regimen of multiple liters of Mountain Dew a day. So we're talking very large, but unfortunately, in a population that there can be some impulsivity, that it's not that it's these, these big changes that can have some important consequences. And so this is one, again, we have an error, so an error therapeutic window. And what does it mean? We talk about risk, benefit being the issue as we as we go up, so it's there's side effects that can occur even as the level gets slightly above 1.2 so 1.2 to 1.5 we can see sedation, weakness, poor coordination and fine motor tremors. So even in what it may be considered goal for some individuals, you could still have side effects. So once again, really want to carefully consider what is the risk, what is the benefit, and get the individual on board. Dr. Sean Kane 21:50 And that makes sense based on what we talked about with phenytoin and valproic acid, that these therapeutic levels are guidelines for you as a clinician. They're not black and white. Once you go above 1.2 you're totally toxic, and you should definitely stop therapy. It's really a patient specific decision, Speaker 2 22:07 right, correct? Now, as we get higher such as 1.5 to three, there's really less evidence that there's much value in trying to target a level like that. We're looking at little bit more severe side effects, such as confusion, agitation, ataxia, so wide base gait, hyperreflexia. And what's interesting about hyperreflexia, one thing I didn't comment upon is the mechanism of action of lithium. Part of it's because nobody really knows for sure. It's thought that it may involve modulation of protein kinases, and then it's also thought it may modulate serotonin release. So once again, I bring that up only because of hyper reflexive we sometimes think serotonin syndrome. And so if one of the mechanisms is modulating serotonin release, then it kind of makes sense, as with some of the any kind of nausea as well. And then at levels above three, get very severe seizures, arrhythmia, irreversible brain damage, even so far as coma or death can occur. Speaker 3 23:00 So I mean, all these things needs to be explained to patients in advance. But with their psychiatric condition, you know, you kind of have to keep bringing them back in the office, because they go on this repeated behavior fashion and might do harm to themselves, right? Speaker 2 23:15 So again, that's where it's part of this, this whole care team. You know, whatever your profession is, it's so important to know the side effects of someone that is working with the population, to know about some of these, about caffeine, know about water, know about some of the things to look for. This is something which we try to and, you know, encourage the social workers, therapists, everyone, everyone that's been working with the neighborhood, Speaker 3 23:36 just know what to look for. So what are the new answers with monitoring the level for lithium in these patients. I mean, when do we draw it? How often? When it's the after dose? I know it's a trough level we monitored, right? Speaker 2 23:50 So it's going to be four to five half lives of the drug. And so what we're looking at, generally, is a 24 hour half life. You want to wait about four to five days. So, so standard for a lot of medications, and once again, 12 hours after the most recent dose, with the goal being a trough concentration. So if you're doing a NINE and a NINE, you may you want to go ahead and get it right that right before that in the next morning's dose. And then, once again, you probably still want to do levels every every six months or every year thereafter. Again, different facilities have different requirements. It's a very good idea that if you know if they're on lithium and you're getting a serum creatinine again, why not get this to go with it? Speaker 3 24:25 So just wrapping up today's episode, going to highlight a few things about tychrolimus. It's an immunosuppressant used as an anti rejection medication. It has we shoot for a common goal of anywhere from five to 20 nanogram per deciliter. However, depending on the type of organ that is transplanted, this goal is different. Should really leave it up to the transplant team to decide that the higher level, most common issues that you can see, or toxicities you can see, are the nephrotoxicity or neurotoxicity such as seizure. Or blood vision, hyperkalemia, nausea, vomiting, increased blood pressure and heart rate, obviously, at the same time, if the level is low, you put you're putting patient at a high risk of organ rejection. Speaker 2 25:12 And then with lithium, you want to make sure, first of all, that you're using the right frequency if you can of dosing. So if you're using extended release product, that you're doing at the ID dosing, so that we can accurately capture the trough and correlate it, so we're not looking at too high of a C max. Second thing we want to look for is that goal of point six to 1.2 and you can, you can consider 1.2 to 1.5 as a gray area where it's about risk benefit. What's the benefit going to be the patient? Is this really going to make their symptoms any better? And are we setting them up? Setting them up, though, for some acute side effects? And lastly, you want to be really careful about looking at these over the counter kind of natural medications. And in this case, lithium is going to likely going to be just as toxic or just as problematic if you're using it as as their amazon.com order as it would be in inpatient. The worst is we don't really know. There have been no efficacy studies on that. All right, Dr. Sean Kane 26:07 with that, we'll go ahead and wrap up today's episode. If you haven't done so already, we'd really appreciate a five star review in iTunes. We've gotten a few recently, and we really appreciate all of those. The more five star reviews we receive, the easier it is for other listeners to find us in the iTunes store. If you want to contact us, we're available at HelixTalk.com where you can also view an archive of all of our episodes and get our contact information with that, I'll sign off. I'm Dr. King, I'm Dr. shoeman, and Unknown Speaker 26:35 I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 26:38 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.