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. Welcome

Dr. Sean Kane  00:32
to HelixTalk episode 30. I'm your co host, Dr. Kane, and I'm Dr. Schuman and Dr. Patel is not with us today, we'd like to wish her congratulations on her recent wedding in marriage. Today we're picking up where we left off last time with Dr. Patel, where we're reviewing some key drugs that are involved in therapeutic drug monitoring. And Dr. shoeman, I know you weren't available. I know that you were doing some pretty important things. Maybe you'd like to tell the audience a little bit about it, and we can jump into one of the drugs that you selected as some of the more interesting drugs for therapeutic drug monitoring.

Speaker 2  01:03
Thank you. Dr. Kane, so had the opportunity to take two of our p2 students with me on a trip to Honduras, where we were able to work with a Medical Brigade there and run an ambulatory care clinic. Great opportunity. Highly recommend these kind of externships as a way to really look at the site of pharmacy that you may not get access to, to be able to work with formulary management, work directly with providers, with the individuals you know, do some translations, and really stick with with one village and hopefully transform that area. And so I was, again, great opportunity, but excited to come back here now and look at one medication, Dr. Kane, that I think both you and I have worked with, albeit from different angles, and that's going to be valproic acid.

Dr. Sean Kane  01:47
So before we jump into valproic acid, I wanted to kind of kick us off with the confusing brand and generic names of valproic acid. So Dr. Sherman, as I understand it, there's at least two different salt forms of valproic acid, divalproc Sodium valproic acid, and depending on your dosage form, you can get one the other or even mixture of both of them. Is that right?

Speaker 2  02:08
Yes, it is. And there's even a another salt form that's not available in the US. And so we'll just kind of stick with those that there's valproic acid or depoken, there's a syrup form as well as an immediate release form, and that one is generally dosed twice a day. And then you have the divalent cation form Depakote, which can come either as a sprinkle capsule or as its own, somewhat of a delayed release formulation. And this is done to help with some of the GI upset that would occur from just taking the velcro gas. We'll get to the side effects. But one of the main ones had been gi opposite. So by slowing down the release, they were able to avoid that that was also given twice a day. And then the one that generally more well known is your dival Pro X extended release, or your Depakote er. And this is the one that that Abbott came out with a few years back and did a whole extensive PK studies to find that it is, can be, can actually be given once a day, although with that, it actually only has a little bit smaller bioavailability, so it's about 80% relative to the other drugs. So a kind of interesting fact is you may need to do somewhere between a 10 to 20% dose increase. Should you go from one of those other forms, the extended release form.

Dr. Sean Kane  03:22
Then, of course, in my neck of the woods, we have depakan, which is the IV formulation of valproic acid. So we have Depakote, depakeen and depacon. And as you mentioned, there's a lot of different dosage formulations, extended release, delayed release, sprinkles, syrup. So I can understand how it would be very confusing when pharmacist receives a prescription, as an example, to really figure out which one is the correct one. And it's probably an opportunity for medication error as well.


Speaker 2  03:51
And that's definitely this is one where it's, you know, when in doubt, get out that that orange book, or go online and start, you know, looking, just to make sure we're looking at something that's rated as equivalent. If you don't, you know if maybe part of the name is a little unclear.

Dr. Sean Kane  04:03
All right, well, great. So we've kind of covered brand and generic dosage forms, at least in your experience, what do you see valproic acid commonly used for? So this

Speaker 2  04:11
is one, and it's interesting, where it's commonly used, where it's FDA approved, or a little bit different. So in my neck of the woods, I see it for its FDA approval for treatment of acute mania or mixed episodes with bipolar disorder, maybe with psychotic features, maybe without. But then it also has a lot of some benefit in treating bipolar depression, and then is also for use in maintenance episodes. And in these cases, it doesn't really have the again, they didn't pursue the FDA labeling. In fact, the FDA really didn't do a lot of approvals for bipolar depression until the antipsychotics, the atypicals, started coming out, but it's very commonly used. Here you look through most of the guidelines put out by the Texas Medication Algorithm Project, the American Psychiatric Association, they generally regard valproic acid very highly in these cases. Then, of

Dr. Sean Kane  05:00
course, it's also an antiepileptic so we can use it for generalized tonic-clonic seizures. We can use it for partial seizures and also absence seizures. So it's kind of a jack of all trades, if you will. Unfortunately, it has some pretty negative side effects that, at least in the epilepsy arena, many of those can be pretty serious side effects that make it so patients don't really want to take their medication. And I would assume in the psychiatric field, that might even be worse.

Speaker 2  05:29
Yeah, it is. And this is one, and the one thing to add too is it's also, again, don't see it as much for it because of the side effects, but can be used for migraines as well as that approval. But once again, because of its side effects, there's other medication they generally go to and those would be alopecia (hair loss, hair thinning), dizziness, some hematologic abnormalities. I've seen thrombocytopenia, leukopenia, and I've even seen a couple patients with pancytopenia, where it generally just knocks around all the different lab parameters you may see. Uncommonly, some of your urea cycle disorders, and I think this is one that can be a little bit scary. Start to see hyperammonemia, with or without hepatic encephalopathy. And in this case, you're kind of looking for lethargy, vomiting, mental cloudiness, hepatic impairment, so your AST, ALT, weight gain, somnolence, tremor, common, upset stomach, nausea, vomiting, diarrhea, ataxia. And then there's some issues, of course, with pregnancy with folic acid. And then there's a little bit of a controversial risk of PCOS. Not every study shows it, and it may be fairly rare, but it generally in combination with the pregnancy catalyst. There's a lot of avoidance of this medication for especially for young females.

Dr. Sean Kane  06:45
So you went through a lot of adverse effects. And unfortunately, many of those are not uncommon adverse effects. So they're definitely seen just to focus on a couple of the box warning adverse effects. It does have a boxed warning against its use in pregnancy, specifically against its use as a migraine preventative therapy in pregnancy for someone who, let's say, has a seizure disorder, is kind of a risk benefit, it's a pregnancy Category D, and also it has a box warning for hepatic failure, mostly in children, but we definitely worry about hepatic damage With valproic acid, it's rare, but serious and can lead to mortality. So that is also a box warning for the product,

Speaker 2  07:27
certainly so. So because of this, you know, we take this medication very seriously when we do begin. I kind of consider it to be one of our, you know, our heavy hitters, especially in terms of an individual with acute mania. So we generally recommend, you know, similar dosing, I believe, to where it's seen in epilepsy, where you can start out 15 MiGs per kid in one to two divided doses, again, depending on which one of those salt forms you're looking at, and you also may empirically. And I think we do this some start at 1000 milligrams as just a one time bedtime dose of the extended release. Or even there have been a few studies coming out recently for for severe mania, that you can do almost a loading dose, and start out with 20 to 30 milligrams per kilogram per day for about five days or so, and then you can bring it down maybe to that, that 15 MiGs per kick. And then there's a nice round 60 MiGs per kick per day. That is the the max. So you have kind of 15 to 60. So again, nice and, you know, divisible by four. So I think for the students now, there's a nice way to kind of remember how the range of dosing is for this medication.

Dr. Sean Kane  08:31
And in general, that's pretty much the same dosing range that you'll see for epilepsy as well, that 15 to 60 ish. Clearly there's going to be patient specific factors that would go outside of that realm, but that's a general rule of thumb that is pretty consistent and probably also a little bit frustrating if you think about it, because you would think that maybe there would be a difference in how you would treat epilepsy versus the dose that you'd use for bipolar disorder and vice versa. But at least in the packaging, there's not good discrimination of this is the best dose for epilepsy, this is the best dose for bipolar disorder, which is both good and bad. I think, oh

Speaker 2  09:05
yeah, Dr. King, you're definitely picking at something that I'm very passionate about. Real quick. First, I want to say that there are some drug interactions we do have to be careful of. This is one that is affected by some plasma protein binding. So if some medications that can displace it. You can also watch. It can be in it can itself inhibit metabolism, so it can inhibit phenotype or phenobarbital. It's in itself inhibited by aspirin, fluoxetine or flu box amine, so the latter two being some antidepressants you may see in combo with. And then, interestingly, that risk of hyper anemia can increase with with Topiramate. And once again, if you're using it as a one two punch for really severe migraines, or if you're using it as, at least sometimes, say, for an individual who has bipolar disorder and migraines, and maybe they were on Topiramate before, which, again, does not, don't, I don't need to get started on topiramates, in effect, in the. For bipolar disorder, so if they have migraines on Topiramate, bring on by valproic acid for bipolar disorder, sometimes start to see the rise in ammonia, and you have to be really careful of that.

Dr. Sean Kane  10:10
Now, is that symptomatic hyper anemia? Because I know sometimes with valproic acid, you can see almost a benign hyper anemia where they don't have the symptoms associated with an elevated ammonia level. But on blood chemistry, they have a high level.

Speaker 2  10:25
I've seen both. We had one individual that was started on, he was on to pyramid, and they started him very quickly, actually, on lithium plus valproic acid soon after. And that triple combination fairly quickly, ended up seeing a lot of cloudiness, a lot of stumbling check the ammonia level, and it was elevated. Since it was symptomatic, we ended up backing off of the death

Unknown Speaker  10:47
program. Yeah, excellent.

Speaker 2  10:49
But again, to get to the big issue is, what about therapeutic drug monitoring? And as you mentioned, Dr. Kane, this is one we have some information about epilepsy, and does it correlate over to treatment of bipolar sort and as I was preparing for this, I was really excited to come across a few names that were known to me as a student at UK so Mary Ansem and George Davis, a couple names that wrote an algorithm, if you will, that looks at whether or not any medication warrants therapeutic drug monitoring, if that's something that can be done as routine standard. So they wrote their paper in 1998 and then a follow up paper in 2010 by Heyman and some looked at extrapolation of valproic acid. So we can kind of look at it based upon these criteria, and then see, does, does valproic acid meet them? So the first one, you know, is the patient on the best drug for the disease state, and as we mentioned, valproic acid does have that effectiveness for bipolar mania. As far as maintenance, it didn't quite meet, you know, the FDA criteria, so it wasn't approved, although that may have just been a factor of the times, except that, and then some recent studies have shown that maybe it's not as good. So it may be effective for maintenance, not as good, but it still has that clear cut evidence for acute bipolar mania.

Dr. Sean Kane  12:07
So Dr. Shireen, just for the audience, could you kind of distinguish between, what is the difference between bipolar mania and then maintenance therapy? Certainly.

Speaker 2  12:15
So when you have an individual who has a decreased need for sleep, some grandiosity thing. You know, I'm the president. I own this company with some delusions. There flight of ideas, racing thoughts, grandiose, impulsive. We label that as as a manic episode. And so in those situations, it's very important to address it, because with that impulsivity can come risk taking, suicidal thinking. And then that's generally the point at which somebody presents. It's when the family members notice it and say, you know, this is out of character, out of ordinary. It's, it's, you know, I may be scared. So bring the individual in. We address the symptoms acutely, somewhat more aggressively. And then once the symptoms remit, you're let you know, then come bring to someone who's euthymic So they're neither manic nor depressed, and then from there, the point is to prevent further episodes, either of depression or mania. So at that point, you're entering into the maintenance phase.

Dr. Sean Kane  13:12
So if I understand it correctly, you're saying that valproic acid has better data for its efficacy against this manic episode, and not as good data for preventing a relapse.

Speaker 2  13:23
Yes, further episodes and again, with remain these medication. It gets trickier at that point, because even the definitions of what is the goal of maintenance again, to prevent relapse of episode, of the same episode or a different episode, and that's maybe it's on topic. But this so the second question is we again, we know that it's the best one of the better drugs for the disease state is the drug readily measured. And we know that the free plasma level correlates well with the free CSF level. And that again, applies both you in the world of epilepsy as well as in psychiatry.

Dr. Sean Kane  13:55
Do you commonly obtain a free level, or is it usually a total level?

Speaker 2  13:59
We do not. We generally get a total level. Again, there's some criteria, if you know that the individual has you know if you've had issues within the response in the past, or if you maybe know there's a gross abnormality of their albumin or some of the proteins that may affect binding. But in general, we stick to a total level.

Dr. Sean Kane  14:18
I only bring that up in Episode 29 we talked a lot about phenytoin with free and total phenytoin levels. In the world of epilepsy, at least, phenytoin has the best described data on the differences between free and total converting between the two and things like that. In general, there's a lot of other anti epileptics and even psychiatric medications that we know have a difference in free and total binding levels between different patients. But for historical reasons, we just don't have as much data to help us discern and describe. You know, what is good free valparic acid level versus a good total one? Most of the data is going to be with the total direct levels for many of these medications

Speaker 2  14:57
right now. What they did is, is they sent. We said, well, based upon the well stirred model, therefore, even though you may see some changes in the total that the free generally is fairly consistent, regardless of any of these displacements. So then another point we can look at is has a good relationship between the drug concentration of pharmacologic response been reported in humans. Dr. King, what's what? What does it look like in epilepsy?

Dr. Sean Kane  15:23
Like most of our anti epileptics, the the idea of a therapeutic drug range is based on retrospective data. Usually it's a scatter plot, and it's kind of arbitrarily picked as a range, as opposed to really high quality data that discerns. This is definitely the point at which you have an anti epileptic effect, and this is definitely the point where the risks outweigh the benefits. I always tell students that the idea of a therapeutic range with any anti epileptic is a guideline, not a black and white issue, and the reason is that certain patients are going to respond differently, have different amounts of adverse effects and things like

Speaker 2  15:56
that, right? So we have, you know, a little bit of evidence for for its use in epilepsy, and a response curve, so we may be able to apply that so. But the next point is, can't can it be measured in other ways? Can you look at somebody and say, Aha, they must have a therapeutic level of Depakote or not? We do have scales like the young mania rating scale, which does correlate pretty well with resolution of symptoms. However, in the world of treatment of mental illness, there's always polypharmacy ruining its head, and so it can be difficult to tell you know, is this person spontaneously getting better? Is it due to the benzodiazepines I'm throwing on board? Is it the antidepressant? Is the antipsychotic? Is it the other seizure medication? Is it just the overall change in environment? So there's many other factors make it hard to predict. So, you know, we maybe a level would be useful there and then, just to dovetail from talking about epilepsy to bipolar disorder, has a good relationship between drug concentration and pharmacologic response been reported in bipolar disorder, and this is kind of the name of the game right now. What we do know is that level of 50 to 100 mics per mil, that's that's generally we refer to for epilepsy had been used in, again, some some smaller studies. And when they went to approve this agent for bipolar disorder, they they stuck with the same guidelines. And so it's just been grandfathered in, if you will, initially. And they did find that maybe in mania, that these numbers can correlate. There was a really neat study that came out just a few years ago looked at 374 patients, and what they seem to suggest is a linear concentration response relationship with a target of about 94 mics per milliliter, that if you reach a level at that that high, then you may see the best benefit, and that as you go up higher, you still see more benefit, but then there's, there's maybe more of a risk of adverse effects, whereas at lower levels, you see less benefit. And again, that was in acute mania. So we have even less evidence for what we're doing in these maintenance episodes, but we do know that, you know, the 50 to 100 was kind of a shot in the dark based upon the epilepsy data, and really, we can target the higher end of it in mania. And some of the guidelines will even say as high as 125 depending on the nature of the symptoms. And that's what a lot of the guidelines will say. And then do, do the levels correlate with safety? And we talked about Dr. Kane about some of the side effects of these medications. And what we do know is that there's a fair number of side effects that are dose dependent. Some of the hematologic abnormalities may be dose dependent. Weight Gain may be dose dependent. Somnolence, tremor, upset stomach ataxia are generally regarded as dose dependent. However, there's a few others that may not be, I think, and generally, from what I've read, hepatic of impairment doesn't appear to be dose dependent, neither does any of the urea cycle disorders, the dizziness and even the alopecia. So we do have some ability to use those numbers to then guide the risk of some of those side effects. Few other points to look at as we're going through. You know, does valproic acid meet criteria for therapeutic monitoring? Does the drug have a narrow defined range, fairly narrow, but again, it's it's wider and less clear than, say, lithium, which we'll be talking about in a future episode, which has a fairly narrow window and a little bit of a better cut off points at this level, someone is better at this level for treatment of mania, and at higher the risk benefits are shifting. Just to round out, the few other parameters are the pKa parameters unpredictable. Well, absorption is not distribution, not really, although you have to aspirin and free fatty acids may displace viproic acid from binding sites. But again, the free concentration won't change based upon the well stirred model metabolism and excretion, well, maybe based upon age and drug drug interactions, that could change. So there's some unpredictability. Is intended. Duration of therapy, long enough that a patient would benefit from therapeutic drug monitoring. In this case, we're talking about some of these medications an individual may be on for life. So. This is that the one point that it is really starting to switch in favor of monitoring, you know, if you have a medication that does have a level, we can get a fairly reasonable idea about, you know, what's considered high and low. So maybe it's, it's worth getting, getting the levels. And the one thing we do know is, you know, do the assays make a difference? And again, this is kind of the one sticking point is at the low end, and the high end is where valproic acid level in mental health issues has its utility. At a low level, you think, okay, maybe the patient's not taking this medication. So it's not always necessarily for whether or not that level is magically high enough. You know, if a level is 50 versus 60, it doesn't necessarily let you know, okay, this patient must be doing better or worse, but if a level is undetectable, or if it's 10 or 20, gives us a fairly good idea that there's questionable adherence to the regimen. And then if you see a concentration that's very, very high, we start to be concerned about if there's any metabolism issues. And we started looking for side effects as well, but again, in between, as long as it's within that range, you know, maybe 7080, 90, at that point, it's hard to necessarily say whether a small spike in the dose would necessarily be better. So that's kind of where we're at with with Depakote, is levels can be good, not always for the same reasons, not not always to you know, if you get a level and it's decent and the person seems to be doing well, it doesn't necessarily warrant that that frequent follow up to keep it within a set, defined area. You just if something changes and an individual starts to maybe decompensate, you may want to get a level and check for that adherence.

Dr. Sean Kane  21:37
We're very good to kind of wrap up today's episode. I'd like to finish off with talking about digoxin, specifically with therapeutic drug monitoring of digoxin, just as a brief review, brand name, lanoxin, and it's actually indicated for two different things, and from a therapeutic drug monitoring standpoint, those two things are pretty different. So one indication is for control of ventricular rate, or heart rate in patients who have atrial fibrillation or afib. And what's going on there is that it actually increases vagal tone, meaning that it increases the amount of parasympathetic tone that a patient has. So it makes it so that the AV node slows down conduction. So it's harder for the atria that are beating really, really fast because they're in a fib. It's harder for those impulses to get down to the ventricle, so the ventricle slows down, and makes your heart rate slow down. The other indication is for systolic heart failure. So this would be in any patient who has an ejection fraction below 40% and what digoxin will do for those patients is it actually improves contractility. It's kind of complex how it works, but essentially what happens is it inhibits a pump called the sodium potassium ATPase pump. So it means that more sodium hangs out in the cardiac cell. And it turns out that sodium is kind of like currency for cells. So because it has more currency, more sodium, using a different pump, it can use that sodium to get more calcium. So buys more calcium with sodium, and that calcium is used to improve contractility. So calcium is highly involved in the contractility of the heart. So more calcium means more contractility. So in those heart failure patients giving digoxin will improve contractility. So we have two different indications, two different mechanisms, and kinetically, they're pretty different if you think about the two different indications.

Speaker 2  23:26
So Dr. Kane has you know different medications have a couple different phases in terms of an alpha and a beta phase, or maybe an absorption phase and a distribution phase. What is, what does digoxin look like in terms of these kinetics.

Dr. Sean Kane  23:41
So digoxin is incredibly interesting in its distribution phase. So usually, when you have a drug and you take it orally or IV, the distribution phase is fairly quick, meaning that it will distribute to its target tissue or whatever tissue, fairly quickly, probably within an hour or two. With digoxin, though it can take a number of hours anywhere from six, eight or even 12 hours, depending on the reference that you look at, meaning that you take your dose, and it takes up to eight to 12 hours for that digoxin molecule to get into its target site in the cardiac tissue. So that's relevant, because sometimes, especially in the hospital setting, we'll use digoxin acutely for heart rate control and someone who has what's called atrial fibrillation with rapid ventricular response, or Afib with RBR, just means that they're in AFib and their heart rate is going too fast. What we do for those patients is we give them loading doses of digoxin. The issue, though, is that because it has such a prolonged distribution phase, it actually takes a number of hours to really see the peak effect of giving the loading dose that we give. So for that reason, we actually split up the dose every four every six hours, and give a couple doses to kind of see what the effect is. And if we still don't have the desired effect, we'll give more drug. But we actually wait a number of hours because of this prolonged distribution phase.

Speaker 2  24:59
And. Is this a medication that hangs on for a while?

Dr. Sean Kane  25:02
It does, and that's the other thing too, in thinking about the peak effect of it, if you have great kidney function, the half life is going to be a day, maybe two days. So that means that your steady state for a normal, healthy person, is going to be anywhere from, let's say, five to 10 days. But if you don't have good kidney function, if you have chronic kidney disease as an example, your half life is going to be somewhere between three and five days, which means that your steady state concentration will take about a month to get to. So if you think about waiting for the peak effect of a drug after a dose change, as an example, waiting a month is a pretty long time to get back to steady state. But that also means that when you're drawing digoxin levels, if you have someone with chronic kidney disease, you have to wait a month after you change your dose to really see the impact or the effect of that dose change.

Speaker 2  25:48
And I know this is a medication that definitely has a narrow window that kind of that's been something, at least for me, it's a concerning thing. I know when I was in Honduras last year, we had someone who came with a prescription from an outside provider for it was a pediatric dose, a very, very small dose. And they wanted it was, I believe it was in a compounded form, and they were looking for us to provide that. And I looked at what we had, I believe we have the point 125, milligram doses. And I'm looking at that and looking at the dose they need. And thing, you know, there's no way I can safely, you know, crush this, put it in simple syrup, and magically know that I'm going to get the right concentration to keep this kid safe. So I think in that case, you they had a provider. And so to see if there's any way we get it, you know, financially help them to be able to go get it elsewhere, this is not one that we, I was willing to make and mess around with.

Dr. Sean Kane  26:37
Yeah, absolutely. So really, to reflect on your anecdote. You were worried about the therapeutic window, right? Oh, very much. So absolutely. So in thinking about the therapeutic window, it's narrow in the sense that if we overdo it just a little bit, we can end up in trouble with the patient. So generally speaking, when we get it to Jackson level, anything above two is considered a toxic level, and we'll kind of get more into the levels, but the reason it's toxic is because of the adverse effect profile. So even though low levels may be worrisome, they're less worrisome than, let's say, an anti epileptic, where a patient may have a seizure if their level is low with digoxin, kind of the worst case scenario is they have palpitations because their heart rate is going too fast, or if they have heart failure, they kind of decompensate. But I think that comparing that to, let's say, a seizure or warfarin, having a pulmonary embolism, I think that really we're more worried about an elevated drug level than a low drug level. With digoxin, one of the other reasons that we monitor, aside from the narrow therapeutic window, is that it does have renal elimination, so typically, this is given in elderly patients. Elderly patients are more prone to acute kidney injury. They're also more prone to drug interactions. So we do see drug interactions primarily because of P glycoprotein inhibition. So as an example, there's really good data showing that if you are on digoxin and you are given amiodarone, your digoxin level will double. Think about that for a second, going from, you know, 1.5 to three for your digoxin level, that's a really

Speaker 2  28:09
big deal. That is heat and premium. Any narrow therapeutic window you double. You know, you're playing with fire,

Dr. Sean Kane  28:14
absolutely so. And it's also a relevant drug interaction. So it's not like an HIV medication with digoxin. This is digoxin with another cardiovascular drug that's fairly common in, let's say, someone who has afib. So it's not like you'll never see that drug interaction. It's a pretty big deal in terms of toxicity. Again, we mentioned that a drug level greater than two is considered toxic. When patients are just above two or around two, maybe one and a half to two, they're going to start experiencing primarily GI symptoms, so nausea, vomiting, anorexia, things like that. They may also have some headache, fatigue, confusion, but generally, these symptoms are fairly non specific, meaning that this could be from a number of other things. But for me, this is a really important counseling point, because you want to capture the Jackson toxicity early on versus later on, where they start getting some pretty severe symptoms. I believe

Speaker 2  29:08
it's those pretty severe symptoms, if I remember from school, this is one of the things that stuck with me. You know, those facts that no matter what you do in the rest of your life, you're going to remember, and it was the green Halo vision with this medication is one that sticks

Dr. Sean Kane  29:21
out absolutely, unfortunately, that's a late finding, meaning that once you have that vision change, if you even recognize it, you're pretty in trouble already. So that's why talking to a patient about nausea, vomiting, anorexia is really important. And even if you think about it, if someone, let's say, has they have some food poisoning, if they get dehydrated enough, they're going to get in trouble with acute kidney injury, especially if they're older, more frail, and if they have acute kidney injury, they are going to hold on to more digoxin so they could get dig toxic, even if the nausea and vomiting wasn't the actual symptom of their toxicity, they can get there because of dehydration. So it's

Speaker 2  29:59
better safe than to. To go ahead and get the level just to just to have it out there absolutely.

Dr. Sean Kane  30:05
So then kind of following the GI symptoms that we can see, following the vision changes, or blurred vision or colored vision, really, where the patients get in trouble is where they start having cardiovascular complications of their digoxin toxicity. So this is AV block, meaning that impulses from the atria don't get through to the ventricle. So you have a very slow heart rate. You can have bradycardia separate from the AV block, and then even arrhythmias. And there's a lot of different kinds of arrhythmias that you can have. But the net effect of all of these cardiovascular problems is that you don't have enough cardiac output, so your heart isn't beating enough for you to maintain blood flow to your brain, to your heart, to your kidneys, to everywhere else in your body. So these patients will present basically with cardiovascular collapse because of the complications of their digoxin toxicity. Now, Dr

Speaker 2  30:54
Kane, you, you mentioned again this, I still this is one that when I think about drug levels. I mean, yes, I got to take this one seriously. When do you need to get a level?

Dr. Sean Kane  31:02
So in thinking about levels, there's kind of two approaches. One approach is someone on maintenance therapy, where you don't necessarily suspect toxicity, and in that case, you can get a level, a when it's at steady state, and you can get a level, ideally, at least 12 hours after they took their last dose. The reason is because that prolonged distribution phase, and this is really cool. So as an example, to put some numbers to it, if you gave a patient a reasonable dose of IV digoxin, as soon as you give that dose, their level is going to be something like between one and 10, which is pretty high if you wait that eight to 12 hours for distribution to occur, independent of much elimination, that level of between one and 10 is going to go down to less than one. So if that puts some numbers to why it's so important to wait, you can have basically a 10 fold difference from the beginning of the distribution phase to the end of the distribution phase. So regardless of when you get it, it's a good idea. If you're trying to get a maintenance steady state level you should be waiting that time. On the opposite end, though, if you have someone presenting with bradycardia, nausea, vomiting, vision changes, and you suspect digoxin toxicity, it doesn't matter when they took their last dose, you're going to react to symptoms plus digoxin, plus potentially a high level, even if they're still in the distribution phase, if they took their level four hours ago, you're still going to get a level. And if it's high, you're going to treat it, because there is a risk of mortality associated with digoxin toxicity. It's not a benign toxicity.

Speaker 2  32:30
So if you get a level that's say, eight or nine, you don't think, well, let's just wait a few more hours and we check you treat it right then and

Dr. Sean Kane  32:36
there, exactly, assuming they have symptoms consistent with the severe toxicity, absolutely, we aren't talking a lot about treatment of toxicity, but just to briefly mention, we do have fab fragments, Digi bind and digifab that are quote, unquote antidotes to digoxin toxicity. And just because we have the antidote doesn't mean that we have a 100% cure rate for digoxin toxicity. People still die of digoxin toxicity, even if you give the antidote. But it's nice that we have the antidote so that we can save more patients.

Speaker 2  33:06
All right, so I know we talked a lot about with my medication, Depakote, having a whole host of dosage forms. What do we have out there for digoxin?

Dr. Sean Kane  33:14
So much simpler, we basically have two different tablet forms. We have 125, microgram, 250 microgram. We also have an IV version of it, and we also have an oral solution. But most patients in the outpatient setting are going to be given an oral tablet, either the 125 or the 250 and most patients on the inpatient side, if you're giving it acutely to treat Afib with RVR as an example, you're going to give it in an IV, IV push formulation. In terms of our goal levels, it's actually very interesting in that they're completely different between heart failure and for afib. So if you have atrial fibrillation, you're not going to have much of an effect on ventricular rate until you get to a fairly high level, so probably around 1.5 so anywhere from one to 1.5 is a typical goal for afib, all the way up to two, which, again, is kind of our toxic range. So you really have to push that dose up with heart failure. It's the opposite. So historically, we used to push the dose up, but when the landmark trial, called the dig trial, came out, where they were looking at digoxin for systolic heart failure, they did some analyzes that showed that the higher your digoxin level was, the worse you did with digoxin, whereas the lower your digoxin level was, the better off you were from a mortality standpoint. So right now, if you look at guidelines, you're going to see somewhere between 0.5 and one as a goal level, and it does appear to be harmful if your digoxin level is greater than one, and patients who take it for systolic heart failure. So going back to the dosage forms, it's interesting, and part of it is for historical reasons that we only have the 125 and the 250 dosage form after that digit trial and after it was kind of more accepted that we should be pushing lower doses. For heart failure, there's been actually a push to come up with a new dosage form called the 62.5 dosage form, basically half of the 125 microgram dosage form. Because right now, if you're an older patient, or if you're someone who has impaired renal function, you probably need the 0.0625 or 62.5 microgram dose per day to get to that lower level. If you take the lowest dosage form, it's likely your level will be too high.

Speaker 2  35:27
And I know from looking at the tablets themselves, this isn't something where you can simply ask somebody again, if they're very elderly, oh, just, you know, just go take that little thing and cut it in half. And no worries,

Dr. Sean Kane  35:37
they're very small. So considering the patient population, considering the size of the tablet, and considering that the issue with narrow therapeutic windows for the drug, it would make sense to have that smaller dosage form. Unfortunately, it's generic. Now it's unlikely that that will happen, but it's something that would be nice to have with that said in terms of dosing, as I said, the smaller you are in terms of your ideal body weight, which is based on your height, and also the worse your renal function is, the lower the dose you need. So it's both weight based and renal function based. Historically, we had kind of complex equations to calculate what your dose should be. There's a great algorithm out there, or a nomogram published by Bauman and did a menaco. And this was published in Archives of Internal Medicine in 2006 it's basically a pictorial representation of how to pick the Jackson dose for heart failure. So the algorithm where the nomogram is intended to give you roughly a level of 0.7 and it does that based on renal function and body weight. So it kind of takes the guesswork and the calculations out of the equation. What you'll end up with is either point two, five milligrams a day, which would be kind of the healthy, good renal function, fairly large ideal body weight patient, point 125, milligrams daily, which is going to be your typical dose for kind of the 40 to 60 year old, normal body weight patient, all the way down to point 125, every other day. Or again, half of that tablet, the 0.0625 milligram daily. This is going to be for the elderly, small people, chronic kidney disease, things like that. So this is cool, because it takes some of that guesswork out of the dosing, and there's no math involved, which is always nice too.

Speaker 2  37:17
Yeah. So for the students out there, again, that's maybe a welcome thing to hear.

Dr. Sean Kane  37:22
This is something, if I was a student going on rotation, I would go find that Archives of Internal Medicine, 2006 article, again, published by Bauman and didomenico, and I would print it off and throw it in your peripheral brain, which is the papers that you carry with you in your coat pocket. This is great, because you can come up with a maintenance dose versus static heart failure of digoxin very quickly, without having to fumble with calculators and things like that. Finally, in terms of dose adjustment, so it's great if you come up with that empiric dose. What do you do once you actually have a level? Well, unlike some of our other medications, like phenytoin, is probably the worst offender, we can use linear kinetics, which means that if you have a current level of 0.5 and I want you to be at 1.5 I'll triple your dose if you're at 1.5 and I want you go down to 0.5 I can cut your dose in a third. The problem, though, is the dosage form. So you only really have two, maybe three, dosage form options out there, and for that reason, with digoxin, you may see patients that take a bigger dose on one day and a smaller dose on another day, or they'll only take it on certain days of the week. And this is okay, because if you think about it, it takes a long time to get to steady state, so the half life is very long. And if you have chronic kidney disease, taking it every other day is no big deal, because it takes an entire month to get to steady state. So you can see a lot of different ways to get around the same problem, but it's linear pharmacokinetics,

Speaker 2  38:44
all right. So just to go ahead and give a little summary, a few take home points, when we look at at Depakote, one of the things we want to look at is that it does have a host of different dosage forms, whether you're referring to the valproic acid syrup, the dival Pro X, the delayed release, or the capsule, or the sprinkle capsule. And then we also have the extended release product and and with the extended release product, if we're increasing using that dose and transitioning to it, we need to account for, you know, about a 10 to 20% increase in dose due to the loss of bioavailability with that one. And then we also want to be really clear on the the what the level can do and what it can do. So once again, we can reasonably say that a level of 50 to 100 and that's in micrograms per milliliter, is is a decent target for treatment of certainly for treatment of epilepsy and in treatment of bipolar disorder, for mania, it's it's not unreasonable. Again, you may need to target, with some of the studies showing that the higher doses in the 94 and up range are better. You may want to look at targeting that and then certainly for maintenance, we don't have a clear cut number to target, but if individuals are in 50 to 100 great that usually means you're compliant. Client. And if an individual has a low level, then that becomes a good talking point with for you as a provider, you know, is this patient compliant with their depako and so their symptoms start to wax and wane, potentially indicating this doses. You can use it as a piece of evidence to have that dialog. And if the level is super high, we have some side effects we're concerned about. And then we also want to know, you know, is it potential that there was some sort of a change in terms of drug drug interactions? Yeah.

Dr. Sean Kane  40:26
And in terms of digoxin, a couple key take home points is, I would always educate a patient about nausea, vomiting, other GI symptoms for two reasons. One, it's a sign of toxicity, and two, it could cause the patient to become toxic because of pre renal, acute kidney injury, or Aki from dehydration. So I think that's a very important counseling point. In terms of dosing, there's really only two dosage forms in terms of tablets that are available, so it makes dosing fairly straightforward, but also frustrating. When you're trying to kind of customize a patient's dose, look out for drug interactions like amiodarone, which can double your digoxin concentration. In terms of levels for afib, you're going to have to push a level up somewhere around one and a half. For heart failure, it's the opposite. You want a lower level. It looks like higher levels in heart failure can actually cause increased mortality, as opposed to help the patient with the digoxin. And then finally, in terms of adjusting. You adjust the Jackson based on linear pharmacokinetics. So it's a simple ratio of where is their level and where you want it to be. But you have to keep in mind that steady state can take a very long time for patients who have chronic kidney disease, all the way out to one month once you make a dosage change, so be careful not to kind of hyper adjust when you're not even at steady state for the drug.

Speaker 2  41:40
All right, with that, I guess we're closing out. This is Dr. Schuman.

Dr. Sean Kane  41:44
This is Dr. Kane, and we miss Dr. Patel, but we hope she's studying hard.

Narrator - Dr. Abel  41:49
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.