Therapeutic Considerations of Antiseizure Medications-Drug Interactions and Medications that Lower Seizure Threshold

Drug Interactions and Medications that Lower Seizure Threshold

Video Transcription

I think my disclosures were discussed before, none of them were relevant today. So the learning objectives.  I'd like to cover how we're going to recognize and manage the interactions between anti-seizure  medications and other medications, and how we can mitigate risks that can be associated with medications that lower the seizure threshold.  So I'm going to start with the first of those two topics, how to manage interactions between anti-seizure medications and other medications.  So here's the framework I'm going to use, and a lot of this will actually be similar to some of the topics that Danielle just covered.  So obviously, most patients who are treated with anti-seizure medications will, at some point, be treated for other comorbidities.  This is, of course, particularly common in an elderly population who start to accumulate comorbidities as they age. These interactions can, of course, be bidirectional.  So the anti-seizure medication can have effects on the other medication, and of course the other medication can have effects on the anti-seizure medication.  And when we're thinking about these interactions, it's important to think about both of these directions often at the same time.  As Danielle already expertly explained, these interactions can be pharmacokinetic or pharmacodynamic.  Most of the known important interactions are pharmacokinetic, related to metabolism, affecting drug levels.  Pharmacodynamic interactions can be important, but they're often, A, much more difficult to recognize, much more difficult to study, and much more difficult to measure, because  they do not typically affect the levels of drugs, and they work at typically receptors. And so they're less commonly recognized.  But common examples of this would include, for example, the use of anti-seizure medications  along with pain medications, or psychiatric medications, or sleep medications, medications that are also potentially sedating.  And for those combinations, you can have a combinatorial effect of sedation that would typically be managed in the ways that Danielle just explained in her talk.  There are a couple of more specific interactions. I just picked out one because it's cool, and I thought about it once before, but hadn't thought about it in a while.  There are adverse metabolic effects of valproic acid with olanzapine. These medications, of course, could be used commonly together in certain selections of populations.  And they can lead to a super-linear effect, leading to weight gain and other adverse metabolic effects, effects on LDL, for example.  So I think most of the rest of my talk, though, is going to move past pharmacodynamic interactions,  mostly because I don't have much to say about them, and onto the pharmacokinetic interactions. All right. So starting to narrow this down a little bit.  Antiseizure medications can affect other medications. So this can work in a couple of different ways. Antiseizure medication can decrease the concentration of the other medication.  And this, of course, can lead to loss of effectiveness of the other medication. This will typically occur with our enzyme-inducing antiseizure medications.  I'm going to use carbamazepine as the kind of class example here, but phenytoin, phenobarbital, several other medications, as Danielle mentioned, are in this class as well.  It's important to note that enzyme induction takes time to develop. So when an antiseizure medication is added, an enzyme-inducing antiseizure medication  is added to another medication, it typically develops over days or even longer and is not present on the first day.  And that means it's possible for no effect to be seen over the first few days on starting the medications and then to develop later on.  An example of this broad class of interactions would include the effect of carbamazepine or other enzyme-inducers on oral contraceptive pills. There are many, many examples of this.  I thought about putting up some tables. I'll just say frankly now I couldn't even fit the tables onto my slides in a readable way.  And so I'm not going to be going through a detailed list of every medication that can be affected in this way by enzyme-inducing antiseizure medications.  Instead, I'm going to focus a little bit on how to manage specific types of interactions. Conversely, we can have increased concentrations of other medications.  And this can lead to side effects or toxicity. Unlike with the enzyme induction case, enzyme inhibition typically takes effect immediately.  The clinical effect may still take time to build up. That depends mostly on the half-life of the affected medication.  But often, interactions taking this form will appear more quickly than those that are caused by enzyme induction or reduced concentrations of the affected medication.  An example of this, another one that I had thought about once before and forgotten about, valproate can actually increase the level of nortriptyline by about 50%.  And so this could potentially, nortriptyline is a medication with a number of side effects. And this could, of course, potentially lead to increased sedation, for example.  A similar effect, increased side effects or toxicity, can be seen in a different situation. And that's with withdrawal of an enzyme-inducer.  And this is something that we often forget about. Because when an enzyme-inducer is added to another medication, the level, the effect of that medication will decrease.  Sometimes that enzyme-inducer is taken away. We're trying to get our patients off phenytoin, off of phenobarbital for various reasons.  That can then lead to them developing an unanticipated consequence of side effects on one of their other medications. And it's important to look out for those. All right.  So switching to the other case. Other medications can affect anti-seizure medications.  This can, of course, lead to decreased effectiveness of the anti-seizure medication, leading perhaps to a breakthrough seizure. I'll come back to this example a little bit later on.  But ritonavir can decrease lamotrigine levels by approximately 50%, a clinically significant amount.  Or they can increase the concentration or the pharmacologic effect of anti-seizure medications leading to side effects.  And another one that I thought was interesting that I don't think about very much, omeprazole can actually increase the levels of the clobizam metabolite.  Again, as Daniel described, not clobizam itself. And this could potentially contribute to side effects.  So I'm going to describe, you know, I mentioned I wasn't going to talk about individual drugs.  I'm going to describe two or three broad classes of medications where these types of interactions are particularly relevant.  And then I'm going to move on to a few brief case examples and just talk about how I think these could appropriately be managed. So chemotherapy is a common example.  The particular problem here is that enzyme-inducing anti-seizure medications, the ones I've mentioned previously, can accelerate the metabolism of several chemotherapeutic agents.  Velproate, conversely, can lead to decreased metabolism and potentially to significant toxicity.  So in these types of cases, chemotherapeutic agents, of course, are typically clinically critical. Often, there are no equivalent or superior alternatives.  This is often a situation where alternative anti-seizure medications should be used if possible.  In particular, we try to avoid enzyme-inducing anti-seizure medications in patients with cancer.  Note that temozolomide in particular, which is a common medication used in patients with primary glial neoplasms, is not affected.  And so these considerations may sometimes be less relevant for primary brain tumors than for metastatic or non-CNS cancers.  Another broad class of medications are two broad classes of medications where we worry about these interactions are psychiatric medications, in particular antidepressants  and antipsychotics. Enzyme-inducing anti-seizure medications, in particular, can increase the metabolism and potentially decrease the effectiveness of many of these medications.  In these cases, it may be appropriate to monitor for clinical effects. Measuring concentrations of a psychiatric medication has not been shown to be helpful  and is not entirely clear if these interactions are clinically relevant. However, pharmacokinetic modeling and measurements do suggest that the degree of change may be  sufficient to lead to clinically significant impact on the patients. In these type of cases, there are a few different approaches that could be taken.  The psychiatric medication could be titrated. It could be increased to a higher dose to compensate for the interaction.  Alternatively, anti-seizure medication could be switched to an alternative, for example, Motrigine, which typically does not cause these types of interactions.  So I'm going to give what I hope is a relatively systematic approach to managing interactions once they've been recognized.  So a few questions you have to ask yourself and then different clinical scenarios. I have four or five different clinical patient, I guess, vignettes on here.  I'll have what I think are the answers on the next slide. Obviously, this is primarily my opinion.  So the first question I would ask is, for how long will the non-anti-seizure medication, the other medication, be used?  If it's a short-term medication, then you should consider a short-term solution, what I would typically call a bridge, a short curse of a medication like a benzodiazepine.  An example of high clinical relevance in recent years is the use of Nirmatrovir, Ritonavir. This is Paxilivir. For COVID, it can actually decrease Lamotrigine concentrations.  As I mentioned a few slides back, this is primarily caused by Ritonavir, which can lower Lamotrigine concentrations. That could be a big problem. That could cause seizures.  But the duration of the use of Paxilivir is only five days. And as I mentioned earlier, this increased metabolism of Lamotrigine can take several days to build up.  So it's a little hard to tell how one would even go about adjusting the dose of Lamotrigine in this situation.  And so this would be a very appropriate scenario in which the use of a bridge, personally I  would use something like Clonazepam 1mg BID, but there are a number of alternatives, could be used to limit the chance of a breakthrough seizure in this setting.  In most cases, though, it won't be a short-term curse. It'll be a longer-term medication. And so in that case, the first question I would ask is, straightforwardly, are there  alternatives to the other medication? So an example here would be a 25-year-old female with seizures that are responsive to Carbamazepine, but not to Levatoracetam.  So a female patient who appears to be dependent on Carbamazepine, but is on oral contraceptives for birth control. So how would we manage that situation?  Next question to ask is, are there alternatives to the anti-seizure medication? In many cases, there will be.  Of course, in all of these cases, we have to balance the risks associated with the potential interaction with the risks associated with changing anti-seizure medication, where the  primary risk is of a breakthrough seizure. So an example here would be a 67-year-old man, chronic Carbamazepine monotherapy, never  tried any other medications, and now he's newly diagnosed with hyperlipidemia and is expected to start on a statin.  Many statins are, in fact, affected by enzyme-inducing anti-seizure medications. The next question I would ask is, can the dosages be adjusted?  And if so, are levels necessary to do this? So an example would be a 16-year-old man, juvenile myoclonic epilepsy, refractory to  levotiracetam and lamotrigine, and he's on nortriptyline for headaches and depression. So how would you manage this situation?  And then a similar example would be a 56-year-old female with drug-resistant epilepsy, three  anti-seizure medications, including Clobizam, alluding back to the medication interaction I mentioned earlier, now starting Omeprazole for reflux disease.  So each of these has a slightly different solution. I already mentioned the Paxlivid case using a benzodiazepine bridge.  For the young woman who is dependent on carbamazepine but has been on oral contraceptives, I think  the optimal solution there is probably going to be consideration of an alternative form of contraception. An IUD would often be appropriate, of course.  In the case of the 67-year-old man on chronic carbamazepine monotherapy, this is a case where a significant conversation would have to happen.  Typically in this case, I would attempt to switch this patient to a different medication. As Danielle mentioned, perhaps lamotrigine or levotiracetam would be appropriate here.  But this is a scenario where the risk of seizures would potentially increase with such a switch.  And so this is a particular case where balancing of risks and benefits will be important. For the young man with initially refractory JME, the next medication to start in this  scenario would, of course, be valproic acid. If this is the case, I would have a high degree of concern that there would be development  of new side effects related to elevated nortriptyline levels. And so I would consider lowering the dose of that medication.  I didn't put it on this slide, but hopefully people have already noticed that this patient is also on lamotrigine.  If you're adding Depakote to a patient on lamotrigine, you should, of course, also pay careful attention and typically lower the dosage of lamotrigine significantly.  And for the addition of omeprazole to clobizam, as I mentioned, the active clobizam metabolite, norclobizam, can build up.  I would expect this interaction to gradually develop over the course of probably weeks or even months in some case.  This might require empirically lowering the dose of clobizam that's given. Or as an alternative, it might be appropriate in this situation to measure the pre-initiation  level of clobizam and its metabolite and then monitor that level as the new medication  is started so that you know how to appropriately respond to any side effects that develop after the medication is started.  All right, switching to the second topic, medications that lower the seizure threshold. So there's actually a little bit, I think, of ambiguity in what we mean when we say that  a medication lowers the seizure threshold. Typically the medication will increase the chance that a particular stimulus or environment  will result in an epileptic seizure for an individual patient. This can actually refer to a few different scenarios.  It can refer to making a patient who does not have an epilepsy at all have a seizure. And this could potentially occur with normal dosing of a medication or an overdose.  And again, these are different scenarios. Could also refer to increasing the frequency or severity of seizures in patients with epilepsy.  And I think even given these possibilities, there are actually some cases where it's still ambiguous.  So a case that I think many of us will have frequently seen in patients presenting with  a seizure is that first seizure occurs in the setting of a use of a medication that can potentially lower the seizure threshold.  I think bupropion is probably the most common culprit here. And it remains unclear if this is really a provoked seizure in a patient who doesn't  have epilepsy or if it's the first presentation of epilepsy that was perhaps triggered by this external factor, this other medication.  And distinguishing between these possibilities can be quite tricky. So the questions I would ask when we're facing a medication that potentially lowers the seizure  threshold are similar to what I was describing earlier. Again, is the medication truly necessary? How urgent or severe is the condition being treated with the medication?  How confident are we that the medication lowers the seizure threshold? Does it only do it with an overdose or can it do it in normal dosing?  Are there other alternatives that can be used? And once again, what is the duration of the expected treatment? So short term, consider a benzodiazepine bridge.  Long term, consider titration of an anti-seizure medication or even addition of an additional anti-seizure medication, addition of another medication.  So if it's likely that an alternative would be available, of course, I would switch if possible. And there are many medications of common concern.  So I'll just mention diphenhydramine and pseudophedrine. It remains unclear if normal dosing of these medications has a particularly significant effect.  And whether or not it's safe for patients to continue using these medications, I think, is often a little unclear.  I would typically take this to be a sign that we should be cautious with the use of these medications, but not that we necessarily need to recommend that our patients avoid them  entirely. So once again, a few common classes of medications, like Michelle was alluding to earlier, that can lower the seizure threshold.  Antibiotics are certainly a common culprit. There are several classes of medications, beta-lactams, cephalosporins, for example,  fluoroquinolones, carbapenems, as was mentioned earlier.  Many of these seem to lower the seizure threshold by inhibiting GABAergic activity, so decreasing inhibitory tone, increasing excitation.  This effect is thought to largely be dose-dependent and to vary with the extent of CNS penetration of the medication.  And in most cases, unfortunately, the degree of risk remains very uncertain. So this is not really a known concern, but something that we worry about. So how would you manage this?  Well, of course, in most cases, the best choice is to switch to an alternative antibiotic if possible. As was mentioned earlier, this won't always be possible.  Sometimes the optimal antibiotic is one that lowers the seizure threshold. The good news is that antibiotics are, in the large majority of cases, going to be a  short course, a time-limited course. And this, again, would be an appropriate situation for a bridge, either with benzodiazepines  or a higher dose of an existing anti-seizure medication. Antidepressants, I think, are a topic that a lot of people have had a lot of confusion  about, including other physicians and patients over the years. So many antidepressants can certainly cause seizures in overdose. Tricyclics are an example here.  Most probably do not at therapeutic doses. At this point, I think it's safe to say that SSRIs have better evidence for being protective  against seizures than they do for causing increased risk of seizures. And this is something that many psychiatrists still seem unduly concerned about.  Bupropion is a counterexample here. So it is well-known to increase risk, and this does append to be dose-dependent.  But the risk does certainly seem to be less using the extended release form of this medication rather than the immediate release form.  And it's actually not clear that when the extended release form is used that this effect is still clinically significant. With antidepressants, treatment is typically prolonged.  However, in my experience, it's rare that an antidepressant other than Bupropion needs to be adjusted. And even this one can be continued if needed.  Extended release should, of course, be used, and anti-seizure medications may require titration. As always, despite what the evidence says, if in a particular patient there is clear  evidence of a temporal correlation between starting another medication and worsening of their seizures, this supersedes all the published evidence, and of course, you should  consider an alternative. And of course, when we're talking about antidepressants, it may be helpful to adjust anti-seizure  medications, for example, Levotiracetam being switched to Lamotrigine, to minimize the need for a higher dose antidepressant. Antipsychotics are another common class of concern.  Once again, most of these are relatively safe. Clozapine is a clear exception here, and it is very clearly associated with a significantly increased risk of seizures.  Olanzapine does this to a much lesser extent. Unfortunately, for patients with refractory psychotic disorders, which includes many patients  with long-standing drug-resistant epilepsy, Clozapine may be the drug of choice. And unfortunately, this is a scenario for which there is no clear answer.  This is clearly a situation in which you have to have a very careful discussion of the risks  and benefits, usually confer with a psychiatrist when making these types of decisions, consider  even starting an antipsychotic in the epilepsy monitoring unit to make sure that the patient is not developing worsening of their seizures.  And once again, prophylactically titrating anti-seizure medications could potentially be considered.  Last, but not least, some medications that could be considered to lower the seizure threshold for some patients include anti-seizure medications.  So this includes, as was mentioned earlier, narrow-spectrum drugs in generalized epilepsy and sodium channel blockers in Dravet.  So I won't say more about that, but please don't forget. So to sum up, there are many risks associated with interactions between anti-seizure medications and other medications.  Fortunately, these can be managed in a variety of ways. Medications can be changed, medications can be titrated, or brief bridge treatments can be used.  Medications that lower the seizure threshold should be avoided if possible. When this is not possible, the risks can usually be minimized with careful adjustments of anti-seizure  medications. Thanks.

Video Summary

The presentation delves into the management of interactions between anti-seizure medications (ASMs) and other drugs, emphasizing the importance of recognizing these interactions, particularly in the elderly and those with comorbidities. It distinguishes between pharmacokinetic (affecting drug levels through metabolism) and pharmacodynamic interactions (often harder to detect, involving receptor interaction). Key examples include interactions with pain, psychiatric, and sleep medications, which can produce sedative effects, as well as specific drugs like valproic acid affecting olanzapine and nortriptyline levels. The discussion highlights strategies for managing these interactions: adjusting dosages, considering alternative medications, and employing bridges like benzodiazepines during short-term treatment changes. The latter part addresses medications that lower seizure thresholds, such as certain antibiotics, antidepressants, and antipsychotics, advising on careful selection and management of these drugs to prevent exacerbation of seizures. The overarching theme is careful balancing of risks and benefits when choosing and managing medications for patients on ASMs.

Asset Subtitle

Presenter:
Michael Gelfand, MD, PhD, is an Associate Professor of Clinical Neurology at the University of Pennsylvania. He completed his fellowship in Epilepsy in 2015. He currently directs epilepsy clinical trials in the Penn Epilepsy Center, and since 2021 has been Director of Clinical Trials for the department of neurology. He also directs the outpatient practice of the Penn Epilepsy Center. He has contributed to 30+ epilepsy trials and has particular interests in rescue therapies, novel diagnostics, and medical and surgical management of drug-resistant epilepsy.

Keywords

anti-seizure medications

drug interactions

pharmacokinetics

elderly comorbidities

seizure threshold