Therapeutic Considerations of Antiseizure Medications-Polypharmacy: Is Less More?

Video Transcription

So now I'm going to talk to you about polypharmacy is less more. These are my disclosures.  The learning objectives for today are going to be to discuss the definitions of pharmacokinetics and pharmacodynamics.  And this is going to be a highlight because I will be honest, I've been attending for almost 10 years, and I think it took about five years to actually understand these definitions.  To evaluate pharmacologic approaches to the reduction of polypharmacy, and also to evaluate non-pharmacological approaches to the reduction of polypharmacy.  And lastly, we're going to assess recommendations for medication reduction after surgery. So you guys already heard this amazing story about Lily.  So I'm not going to go through it as much as Michelle. But again, so right now she's 18 years old. You already heard that she has Dravet. It was a de novo mutation.  You already heard a lot of this. Her first seizure was age four with non-convulsive status epilepticus.  Over the next six years, she had alternating prolonged hemiclonic or generalized seizures every one to three weeks resulting in status epilepticus.  Currently, she has generalized seizures about every three to five weeks. Her EEG in the past showed generalized slowing, poor background organization, and excess beta.  These are her current anti-seizure medications that Michelle just went through as well. And these are the side effects.  And I want you to look through the medications and look through the side effects and keep those in mind as I go through the rest of my presentation.  So we know that we have over 30 drugs on the market, which is great. We have multiple different mechanisms of action.  We have reasons to try different things if they're not working, and we have the ability to do it.  So this is just showing the primary mechanisms of action for anti-seizure medication, sodium  channel blockers, as you know, calcium channel blockers, GABA-related medications, glutamate antagonists, synaptic vessel protein, SB2A modulators, carbonic anhydrase inhibition,  and obviously others that we don't quite know the mechanism. So this is the slide that I want to basically put it in layman's terms. So what are pharmacokinetic reactions?  So this has to do with metabolism. This is the effect on drug absorption or concentration.  So if you have a medication that is an inducer, it's going to induce or speed up the breakdown  of another medication, which means that other medication, the levels of the other medication are going to go down. It also can interact with plasma-brinding interactions.  So again, this is working on the metabolic pathway. This is something that is predictable that we know to look for.  Pharmacodynamic interactions, you can think maybe they're predictable, but sometimes they're not.  But the rule of thumb to kind of think about is this is where if you combine mechanisms of action or if you combine drugs that work on the same receptor, have the same action  in the brain, you are more likely to have side effects. So these side effects can result in excess toxicity. They can limit tolerance.  If you have two medications on sodium, a patient on two different sodium channel blockers, you might not be able to get either of them up to an efficacious dose because they're  having side effects. And it's also sometimes it's hard to avoid, right, especially if you inherit a patient  on a certain mechanism action and maybe it works, so maybe you want to try to combine. Just things to think about. So let's focus on pharmacokinetic.  So I already told you what it was, but here's an example. So an example would be looking at valproic acid and lamotrigine.  So valproic acid is a known inhibitor of UGT1A metabolic pathway. And lamotrigine is actually cleared by that.  So if you are inhibiting the metabolic pathway that clears a med, that med is not going to be cleared. Lamotrigine metabolism is going to be blocked. It's not going to be cleared.  And that's why we know if someone's on Depakote and lamictal or lamotrigine, we know that those serum levels are going to go up.  This is just a list, again, of enzyme inducers, inhibitors, or those drugs that aren't thought to have either.  And I added some extra stars, you know, just to say that not all drugs that are inducers induced at the same amount, right?  So we do have some weak inducers, but those are inducers that you still need to think about. So now let's go to pharmacodynamic.  So I already mentioned to you guys it's drugs that work on the same receptor, the same action in the brain.  So here, to give you guys an example, think about two different sodium channel blocking drugs. For example, you can think of lamotrigine and carbamazepine.  And so because they work the same way, the same mechanism of action, you actually can get an additive effect of the side effects.  So it tends to cause more dizziness and more ataxia. And we see this. And then a lot of times we may take one of the sodium channel blockers down, or we might  not even add a sodium channel blocker if they're already on one. We know that the most common adverse events that are associated with anti-seizure use  are also the most common adverse events that are seen if you have these pharmacokinetic and pharmacodynamic reactions.  Sedation, fatigue, cognitive complaints, psychomotor slowing, dizziness, double vision, headache, it's all been reported as a standalone side effect.  But when you put two drugs together that are going to work the same way, or potentially going to interact with metabolic pathways, you're going to see these side effects.  And these are the side effects that you've got to warn your patients about. Because if they experience it, they need to let you know so that you can make changes.  So we talked about Lilly. So I asked you guys to look at Lilly's drug list and see if you saw any medications that  potentially could have a pharmacokinetic or pharmacodynamic reaction. And when you looked at her side effects, could you see one that could have caused her side effects?  So I'm not going to quiz everybody here. I'm going to give you the answer. So if you saw, Lilly was actually on Clobazam and she was on Epidiolex.  And it's known to have a pharmacokinetic interaction. So just to kind of show you guys what that interaction is, so each of those compounds  actually increased the major metabolic metabolite of the other, so to kind of spell it out. So cannabidiol, its effects on Clobazam are that there's a three-fold increase in the  active metabolite of Clobazam that end as methylclobazan. But it has no effect on the Clobazam level itself, but it does increase the metabolite.  And then Clobazam's effect on cannabidiol was that there's a 47% increase in the active metabolite of cannabidiol, which is the 7-hydroxy cannabidiol. And what can the result be?  Simulants or sedation. And so I can turn to Michelle, but one of the side effects that you saw was tiredness and sedation.  And so that might be something that she's on a lot of medications. But if that was something that was new when one of these meds was added to the other, you want to think about it.  Now that being said, I do also want to highlight that some medications work very well together. They play nicely in the sandbox. Cannabidiol and Clobazam play nicely in the sandbox.  In fact, there's believed to be some synergism if you do have them on together, but a lot of times at lower doses of the Clobazam.  So there's been studies that have actually shown that patients receiving cannabidiol and Clobazam may experience a greater reduction in drop seizures.  And that's not just head drops. That's any type of seizure that can cause a drop. Generalized tonic-clonic seizure, tonic-de-clonic, tonic-clonic, all of those, tonic alone.  So what are my kind of less and more recommendations to you guys? The first recommendation, I'm going through the pharmacologic approaches.  First recommendation, use combinations of different mechanisms of action. So this is a paper that's actually looking at the effectiveness of anti-epileptic drug  combinations for partial onset seizures based on mechanisms of action. The importance, or what was found here, and you can see, is that this paper was the first  to really describe patterns according to patients' mechanisms of action. And what it did is that it actually showed that patients would have better tolerance.  And if they had better tolerance, they had better retention. And so it plays a role in efficacy.  So the take-home message here is that this study found that anti-seizure medication combinations  with different mechanisms of action had greater effectiveness by measuring both the treatment persistence, so if they tolerated it, they stay on it, right?  But it also looked at lower risk of hospitalizations because if they tolerate it, they stay on it.  If they do not tolerate their medication, if they have drug-drug interactions, they're not going to take it, and then they're going to end up in the hospital.  So we have to keep that in mind and make sure that we are addressing this with our patients. Next recommendation, reduce previous medications if they are not working.  So very first thing that's very important. So we heard a lovely talk about picking that first drug.  When you pick that first drug, if you think that first drug isn't working, you've got to think to yourself, well, did I optimize it?  So if you are going to add a second drug, if you're going to move from monotherapy to polytherapy, you need to assess and maximize that first dose.  Make sure, if you can, based on tolerability, make sure that it's not working. And if it's not working, add another drug on.  And if that first drug never helped and was not efficacious, don't leave it on. If you add an alternative drug, then that first drug that didn't work, take it off.  Or if it worked a little bit, and you ended up pushing it up, and pushing it up didn't work, bring it back down to what was efficacious. So that's my next bullet point.  When you put a patient on a drug, document when it becomes efficacious. If it's not working, so let's say, you know, you have levotriacetamine, you're on 1,000  twice a day, and it's not working, and you push it up to 1,500 twice a day, it's still not working, and you're going to add on another drug, add on another drug, but don't leave  the levotriacetamine at 1,500 twice a day, it didn't work. And you guys are going to hear more about drug load, right, and what drug load means for our patients.  And drug load means that they might be more sedated, they might have cognitive slowing, they might have more side effects. So try to reduce that drug load.  So for me, I think it's really important to document, because sometimes we don't remember,  or sometimes the patients go to other providers, and if it's written, it's a lot more helpful.  So again, medications might be titrated up to, you know, the increased efficacy, however, if you increased it, and it did not help, and it was not efficacious, do not leave it  at that higher dose, because you may have more side effects develop, you may have more side effects develop when you add on that next drug because of some drug-drug interactions.  So I know there's a lot of APPs here, and if you guys have ever heard me speak at Penry, I like pearls. I like little nuggets to take home.  If you take home one nugget from this talk, I feel like I've done my job. So my pearls, a little bit that are sprinkled in, are once you're at a stable therapeutic  dose, determine the efficacy, mark the efficacy, remind yourself, you know, they became seizure-free  at this dose, put it in your note, or they, you know, worked best at this dose, but also determine tolerance.  If they don't tolerate it, you know, you have to do something about that. And then if you can, if that previous medication didn't work or only worked to a certain degree,  then try to reduce it. Recommendation three, and you actually heard this already as well, use lower doses in the elderly.  So again, another publication to support these recommendations. So a randomized double-blinded comparison of antiepileptic treatment in the elderly.  Now looking at new onset focal epilepsy, but that's important because you're going to be starting them on a drug, you want to start them on the drug that they tolerate the best,  which was already mentioned. So the significance here in this study was in the initial monotherapy of a focal epilepsy  patient or an elderly patient with focal epilepsy, they looked at one-year retention rates, and  they actually compared levotriacetam to carbamazepine, and they actually had the same efficacy, but levotriacetam was actually better tolerated, so patients did better on it.  They also looked at lamotrigine, and that was kind of intermediate, but levotriacetam had the best tolerance.  All three were similar for efficacy, which we know based on a lot of the data that we have. So what's the take-home message?  Initially dosing, the initial dosing of epilepsy medication in the elderly should be started lower and slower.  Do a slower titration, and also what that will do is that will reduce the risk of having tolerability issues, and it also will increase retention.  Because again, if they don't tolerate it, they're not going to stay on it. And then especially in dealing with elderly patients, think about those age-related declines  in renal and hepatic functioning. That's why I start lower, and that's why I titrate slower.  So the take-home messages for the pharmacological approaches are utilization of various mechanisms of action is key.  If a new medication is started, evaluate and possibly reduce that previous treatment. Reduction of ineffective dosing to improve tolerance and retention.  If you increase the dose and it doesn't improve the efficacy, then ideally try to get it back to the lowest dose that gave the best efficacy.  So again, my little pearl, when selecting or titrating a medication for new onset seizures in the elderly, so some of my go-tos are Lamotrigine or Levotiracetam.  In Lamotrigine, my target dose is 50 twice a day. My target dose for Levotiracetam is 500 twice a day, but I start at 250 and then I go up to 500. Again, you want them to tolerate.  So what about non-pharmacological approaches to reducing polypharmacy? My next recommendation for this, or my first recommendation, is neuromodulation.  So you can see the three FDA-approved neuromodulation devices, the vagus nerve stimulator, the responsive neurostimulation system, and the thalamic deep brain stimulator.  Recommendation number one. So neuromodulation does not produce the same side effects that medications do.  You don't get that sedation, that fatigue, that dizziness, that cognitive slowing. It has been shown that there are improvements in cognition, memory, and mood.  Specifically, there are publications out there showing, for example, the VNS, that there's improved attention and memory.  With the RNS, there's a paper out by Dr. Loring at Emory, and he actually showed improvements in both verbal memory and or naming based on where the RNS was placed.  There's no honeymoon period. Typically, it actually takes a little bit of time to rev up and or optimize the programming  of neuromodulation devices, but typically it gets better with time. So what do all these things lead to? They lead to allowing us to reduce polypharmacy.  So this is another paper or publication to support that. So this is by Larry Hirsch and colleagues.  What they actually did is they used brain responsive neurostimulation, so they used the RNS device to actually show that you could monitor when the earliest possibility of efficacy  is seen. What they actually found, if you look at the significance right here, is in RNS patients, they looked at the detection settings, so they basically had stable detection.  They were not changing detection at the time. When a new anti-seizure medication was added, they actually looked at these detection rates  or long episode rates, and within the first one to two weeks, it was able to provide an early indication of efficacy, and it showed that this early indication of efficacy may  allow us to identify a medication that works a lot sooner and maybe make medication adjustments sooner or faster.  And so the take-home message here is that it allows providers to identify a medication that may work.  You know, a lot of times we'll start someone on a medication, and then they have to stay on it for like three months, six months, because you're waiting for it to work, and if you  can see early on it's not working and they're having side effects, you potentially could try a different drug sooner.  The other thing is, is if someone's on multiple drugs, you can use, you know, ECOGS, you can  use an EEG to basically look at that and maybe take off one of those drugs that wasn't working  or they didn't think was working and look to make sure that the EEG and those long episodes aren't getting any worse and also feel more comfortable reducing polypharmacy.  Recommendation number two, diet therapies.  We cannot underestimate this, and especially in our pediatric colleagues who I think do this better than, I'm an adult epileptologist, so I can say they do it much better than me.  Don't forget about diets. And it's not just about the ketogenic diet, right? That's very hard to do in an adult population. But what about the modified Atkins diet?  What about the low glycemic index diet? We've seen that these diets can help, and if they work, you can then potentially reduce other polypharmacy. Last recommendation, surgery.  What do we do if patients have had surgery? So post-surgical medication modifications. Now, again, this is provider preference, so this is my own personal preference.  But I typically wait about one to two years before making any changes. I think I'm a little bit on the, well, I'm a little conservative. I can say that.  However, if I have a patient who has any side effects from a medication, I am going to take that down sooner. Communicate with the patients.  Make sure you know the history of the ASMs, how it started, their efficacy, their side effects. Sometimes they're on three or four meds, and that other med didn't really help them.  So remember that. Or they're on certain meds that cause more side effects. Solely reduce or taper off of those medications that were least effective or contributed to  the most side effects. So to bring it all together, what is the significance or impact on clinical care and practice from my presentation? Drug-drug interactions are common.  Be aware of them. Think about them when you're changing medications. Be aware of pharmacokinetic and pharmacodynamic interactions and choose drug selection accordingly.  Prioritize the use of drugs with different mechanisms of action. If you have a newly added drug and it's efficacious, great.  The drugs that they were on before you added this new drug likely were not working. That's why you're adding the new drug.  So if you are adding a new drug and there are interactions, reduce the previous drugs that weren't working so that you actually have the ability to optimize efficacy with  the newer drug that you're adding on because you want better efficacy. Use lower doses and slower titrations in the elderly.  Consider non-pharmacologic methods like surgery, neuromodulation, diet therapy. Address the possible side effects and drug interactions with your patients.  If they don't know what to look for, they might not realize that it's actually the drugs that are causing it and they might just deal with it or live with it because they don't  know there's something you can do about it. If you do not know, oh, sorry, you're not going to know if you don't ask.  So when they come back, ask them how they're doing, like ask them if they're experiencing any side effects because they won't always tell you. You have to ask about it.  Ask about tolerance. Ask about side effects. And the last take-home point, by reducing medication, it reduces side effects and ultimately improves quality of life.  Less, in my opinion, is more. Always consider simplifying the treatment regimen. Thank you.

Video Summary

The presentation focuses on polypharmacy, emphasizing the importance of understanding pharmacokinetics (drug metabolism and absorption) and pharmacodynamics (drug action and interaction). The speaker highlights evaluating both pharmacologic and non-pharmacologic approaches to reducing polypharmacy. Practical recommendations include using combinations of drugs with different mechanisms of action, reducing previous medications if ineffective, and using lower doses in the elderly. The discussion also covers the effects of drug interactions, using examples like valproic acid and lamotrigine, and emphasizes the importance of neuromodulation and diet therapies as non-pharmacologic alternatives. Surgical outcomes and medication adjustments post-surgery are touched upon, with a focus on patient communication about side effects and drug interactions. The key message is optimizing treatment regimens to minimize side effects, improve tolerance, and enhance quality of life, promoting the idea that less medication often translates to better outcomes.

Asset Subtitle

Presenter:

Danielle Becker, MD, MS, FAES, is an associate professor at Case Western Reserve University School of Medicine and the Medical Director of Epilepsy at the MetroHealth Hospital System. She has special interests in neurostimulation and women in epilepsy. Previously, Dr. Becker was an Assistant Professor of Clinical Neurology at the Hospital of the University of Pennsylvania for over 7 years. She left her position at the University of Pennsylvania to start an epilepsy program at MetroHealth in 2020. Dr. Becker completed 2 years of neurophysiology/epilepsy fellowship—first at the Hospital of the University of Pennsylvania, second at the NYU Medical Center. She is boarded in both Neurology and Epilepsy subspecialty. Dr. Becker served as the Director of the neurostimulation program for surgical management at the University of Pennsylvania as well as head of epilepsy education. She was also the associate program director of both the Neurology residency and Neurology medical student clerkship and assistant director of the Epilepsy Fellowship program.

Keywords

polypharmacy

pharmacokinetics

pharmacodynamics

drug interactions

non-pharmacologic

treatment optimization