Drugs for Epilepsy

Welcome back to the Ninja Nerd Podcast. Today we're talking all about drugs for epilepsy, talking all about those anti-epileptic drugs. Get ready for a good one here. Zack, first off before we get going, how are you feeling today? Good, man. I'm good. Excited to get cover of some anti-epileptic medications. I think this is a favorite of yours because working in the neuro ICU, you get this a lot, correct? Yeah, yeah, definitely. 100% see this a lot, unfortunately. It's a slightly different approach in comparison to what we're going to talk about here. Hopefully, sometimes soon we'll talk a little bit more about status epilepticus, but usually that's the patient population I see in ICU. There's just multiple AEDs and infusions and comas that we put patients in, unfortunately. There's a lot to learn. As always, everyone, please make sure you go on Ninja Nerd.org. Grab your membership, your subscription. Make sure either it's a three month, a six month, or a year. Get on board. Really grab your notes, your illustrations, and let's learn all about drugs for epilepsy. Today we have to start first getting our groundwork and our foundation set up. Let's move into now the pathophysiology and the causes of epilepsy. All right. Sounds good. When we talk about epilepsy, there's just basically a classification system that we utilize. It really comes down to two, but you can add in this third one for just that education sense, that it comes down to focal seizures, generalize seizures, and then the unknown, which we just group into this epileptic spasm group. Now, focal seizures can actually look a lot different from person to person. Depending upon where the actual focus of agitation in the cortex is, if it's involving the motor cortex, like right motor cortex, you can have left sided abnormal movements. If it's the sensory cortex, you can have abnormal sensations on the left side. If it's involving parts of your temporal lobe, you could have behavioral memory changes, weird smells, you know, things to that affects you. The whole point is that depending upon where the focus of irritability is, we'll determine the type of presentation that you have. And sometimes patients who have focal seizures, they can lose consciousness. We call this focal seizures with impairment. But then you get into the generalized seizures. So these can actually exhibit many different types of characteristics. So you can have what's called a tonic, which is that kind of grandma, scary, shaking seizure, convulsing kind of seizure. Then you can have tonic, they basically their arms turn into kind of like these like rigid pipes, they're really, really stiff. Clonic is they do have this jerky movement, but they're not stiff and jerking. And then you can have a tonic, they completely go limp. Sometimes it actually can look like they're syncopizing. And then myoclonic is this rhythmic, very quick, jerking movement that's very consistent. It is exactly the same almost every single time. And then absence seizures, really sad. You see this in kids who really are kind of just staring out, they kind of blank out in class and forget everything that really happened. There's, there's nothing funny about this, but I do appreciate you guys can't see this, but I'm looking over at Zach and he's acting out each type of seizure. I love, I love the passion and the dedication there. Again, nothing funny about it. I just, I just thought it was cool that he's, he has to go all out. It's the downside of a podcast is you can't have the pictures and, you know, visual representation of things. But but I have to say you make it work. You're with us in spirit. But yeah, that's, that's the kind of basic concept for, you know, your classification of seizures. You can't get into like the epileptic spasm group, which there is many different types with the most common being like benign, Rolandic West syndrome and Linux Gestalt syndrome, which is a really sad one, but that's kind of the basic classification. When it comes down to causes of epilepsy, this is really important because when a patient seizes, right, there's this irritable parts of the brain. Usually if it's focal, it's a specific area. If it's generalized, it's multiple areas of the brain that are become agitated and irritated. So you have to figure out why is that happening? So oftentimes I just like to remember the mnemonic vitamin D E, right? So V for vascular, I for infectious, T for trauma, A for autoimmune, M for metabolic, I for idiopathic, meaning we don't know why. And this is oftentimes those patients who have that chronic epilepsy. We can't find a reversible cause for them. And then you get into endoplasia, D for drugs and toxins and E for eclampsia. It's really important to search through these causes. So whenever you have a patient who has a first time seizure or a breakthrough seizure, you want to go doing some CT MRI imaging, maybe an LP, consider looking into, again, autoimmune diseases. Maybe if you do an LP, you check for any autoimmune types of processes or perineoplastic, sending off metabolic panels, sending off a BMP look for hyponatremia, a point of care glucose to look for hypoglycemia, checking some LFTs to look for cirrhosis, TFTs to check for thyrotoxicosis. Again, CTs will show any kind of neoplasia, bleed, subarachnoid, all these different types of effects. And then again, maybe a drug screen to see if they've taken any kind of illicit drugs or looked at their medical history as well. But those are big, big things. So then we kind of move on to the next part, which is, okay, we know the potential reasons why a patient can develop these irritable areas of their brain, which can cause a focal seizure or a generalized seizure. And we know how they can present. The question is, is why at the neuronal level does this happen? And really, it comes down to two things. One is certain neurons are releasing way too much glutamate. And that could be a really bad problem because glutamate, when it acts on particular cortical neurons, it causes excessive excitability of those neurons, it causes lots of action potentials and then subsequently seizures. Whereas on the other end of the spectrum, there's also a molecule called GABA, gamma-aminobutric acid. This is typically an inhibitory neurotransmitter. So if you have very low levels of GABA or low effect of GABA, this will cause less hyperpolarization. In other words, you won't inhibit the cell. And if you can't inhibit it, it will then become stimulated, generate lots of action potentials and trigger seizures. So the basic mechanism behind this disease is increased glutamate activity and decreased GABA activity. And that leads to these abnormal kind of agitated neurons leading to the presentation of focal, generalized, or sadly, kind of epileptic spasms, Rob. All right. So we have covered the pathophys. We've gotten the causes down and we've even talked about the mechanism behind epilepsy. Now we have to get into the mechanism behind how these anti-epileptic drugs or AEDs for short are really working, working at that neuronal level. So let's get into it. Let's really dig deep here and figure out how these awesome drugs are really exerting their effect. I like it. So definitely, whenever you're thinking about these, remember that basic pathophys, that there is an increase in glutamate or a decrease in GABA. All right. So my job is to give AEDs to decrease glutamate into increased GABA. That's really it. And so the drugs that are going to decrease glutamate activity, I can remember this based upon a couple of different ways. One is on the glutaminergic neurons, there's something called sodium channels. Sodium channels are on the axon. When they open up, sodium rushes in, triggers an action potential that allows for the neuron to fire and release glutamate. If I shut those sodium channels down, I can't release glutamate. That's decreasing glutamate. So these are my sodium channel blockers. This includes carbamazepine, oxcarbazepine, phenytoin, phosphenytoin, lamotrigine, valproate, and topiramate. And if you really want to add another one in there, you can remember lacosamide as well. Then we get into the next group. And this is your calcium channel blockers. So the next thing is whenever, again, a glutaminergic neuron that releases glutamate, right? Sodium channels on the axon allow for sodium to flush in, depolarizes the membrane. When it depolarizes the membrane, it really causes calcium in the axon bulb to flush in via these voltage getting calcium channels. So calcium rushes in into the axon bulb and stimulates the vesicles to fuse with the cell membrane and release glutamate. What if I gave a drug that blocked calcium entry, then the vesicles wouldn't fuse with the cell membrane and release glutamate? Well, that would be a drug called ethosoxamide. So we have sodium channel blockers and we have calcium channel blockers. The next thing is in order for the vesicles to fuse with the cell membrane, they need this particular type of protein. It's called a synaptic vesicle type 2A protein. And if I block this protein from fusing with the cell membrane, then I won't be able to exocytose or release the glutamate. And again, I'm decreasing glutamate activity so I can give a drug that blocks the SV2A protein. And this is called levatorazetam. The next thing is once glutamate is actually released from the glutaminergic neuron, what if I had something that could block the receptor that glutamate binds onto? So glutamate still gets released, but I don't allow it to bind onto the receptors such as the AMPA receptors and the NMDA receptors. You know why? If I block them, I block the entry of sodium and calcium into the neurons, these agitated cortical neurons. And if I decrease the sodium and calcium influx, I don't allow those neurons to depolarize. I don't allow for them to send action potentials and I don't allow for these cortical neurons that are agitated to trigger seizures. And that's where I can give drugs that block the AMPA receptor, which glutamate binds to, called felbamate, or the NMDA receptor called ketamine. All right, so we got the drugs that decrease glutamate activity. What about the drugs that increase GABA activity? So in the same concept, you have other neurons that act on these agitated cortical neurons and try to suppress them, right? And this is GABA. When GABA is released from its cabergic neurons, it binds on to GABA-A receptors. GABA-A receptors will open up and allow for chloride ions to flow into that neuron. And when it flows into the neuron, it's supposed to hyperpolarize that neuron, make it negative, make it not want to be stimulated, and therefore suppress action potentials and suppress seizures in that cortical focus. So if I give drugs that bind onto the GABA-A receptor and enhance its activity, that would increase chloride ion influx, that would cause, therefore, what? If I increase chloride ion influx, I'm going to actually cause more hyperpolarization, more decreasing in action potentials, and more suppression of seizures. So what are the drugs that do this? I want you to remember benzodiazepines, such as lorazepam, medazalim, diazepam. You can also remember a newer drug that's been added on is clonaz-- clabazam, I apologize, clabazam. What I really want you to remember about this drug category is that when they bind onto the actual GABA-A receptor, they really open the ion channel, and they allow for a more frequent opening of that GABA-A ion channel. So whenever benzo is buying, they increase the frequency of how much that channel opens, how much chloride ions influx, and how much you hyperpolarize the cell. The next group is barbiturates. And barbiturates are going to be things like phenobarbital and pentobarbital, very, very powerful drugs. Why are they powerful? Why are they more powerful than benzos? When they bind onto the GABA-A receptor, they increase the opening of the channel, and they keep it open for a long time. So they increase the duration by which that channel is open. The longer amount of time that chloride ions can influx, more hyperpolarization, more suppression of action potentials, and some strong suppression of seizures. How do you remember that? Ben likes it when he gets it more frequent, and barb likes it whenever it's a little bit longer. So that's kind of the way that I remember that, and I was taught that, and it just helped me to remember the basic kind of like extra step there, that benzos, again, increase frequency, Ben likes more frequent, barbiturates, longer duration of chloride channel opening, so barb likes it longer. All right, next thing is we have other drugs that are going to be GABA-A agonists. This is Propofol, a very powerful type of drug, and Topiramate. Now, that might sound interesting and familiar. Topiramate was actually what else? It was a sodium channel blocker, and that dropped glutamate activity. So this drug Topiramate has the ability to drop glutamate activity and increase GABA activity, which is cool. The next thing is what if the GABA that's released from these neurons gets re-uptaken back into the GABA-A neuron? It can get broken down or it can get recycled. What if I actually allow for most of that GABA to stay in the synapse and continue to keep binding to the GABA-A receptors that allow more chloride ion influx, more hyperpolarization, more suppression of action potentials and suppression of seizures? So I'm going to inhibit the reuptake of GABA, keep more GABA in the synapse. That's a drug called Tiagabine. And the last drug class that will actually help to increase GABA activity is once GABA is brought back into the synapse via the reuptake protein, it then can get broken down via something called GABA Transaminase, and that will basically break you down into an inactive metabolite. If I prevent the breakdown of GABA in the neuron, I can make sure that most of its recycled back into the vesicle and most of its released back out into the synapse. So I'm really trying to maintain the amount of GABA that I can release. And that's going to be drugs called GABA Transaminase inhibitors. They inhibit that enzyme to prevent the breakdown of GABA. This is Vigabatrin and Valproate. They're like, "Wait, wait, wait, Valproate." That sounds familiar as well. Wouldn't that a sodium channel blocker? It is. So Valproate can actually block the sodium channels to reduce glutamate release, but it also can increase GABA release. So that's an important concept. And that really covers the mechanism of all these AEDs, Rob. I think it's very important to have a clinical approach to epilepsy when we're talking about all of these AEDs because there's a lot of them. So it's really important to have that approach. And you're in luck because Zach has come up with a beautiful approach to anti-epileptic drugs. And they're going to go, either it's a first line, a second line, or any additional therapies or interventions that you may want to utilize. So Zach, go ahead and take it away. Yeah. So when we talk about epilepsy, I mean, the first thing that you have to figure out is, is there a cause that led to this, right? So you have to go back and kind of evaluate that vitamin D, E thing. And if you can treat it or reverse the underlying cause and the patient stops having seizures, you may not have to give them an anti-epileptic, which is a really good thing. You don't want to expose them to a drug that they don't need. But if you find the cause, you treat the cause, they continue to have seizures or you can't find a cause, it's idiopathic or it's epilepsy in this situation, because you can't reverse the cause, then you need to continue to keep treating them and suppressing those seizures with AEDs. So what we do is we find out what kind of seizure they have, is it focal, generalized, et cetera. And then we say, okay, which drugs are best for that particular seizure disorder? And then we'll pick that drug. Once we pick that, we actually obviously monitor them and see, okay, do they have seizures? Are they persisting? Or are they free of seizures? If they continue to have persistent seizures, or they have really nasty reaction to that actual AED, then we switch. We try another one. So we'll try something else. So now we'll call that the second AED, and then we'll start down titrating the first AED after we do that. And then we'll see, okay, does this AED better? Does it suppress the seizures? Oh, it does. Good. Well, then we found the drug. Does it not suppress the seizures? And so they still have seizures, or they have nasty adverse drug reactions to that one? Okay, well, that's not the drug then. Well, then the next thing I got to do is I got to see, okay, is there an alternate drug? So is there a third AED, another one that I can consider? Or do I need to do combination therapy? Do I need to give them two AEDs to suppress these seizures? And if that's the case, then I'll try that. And if they're seizure free, great, I've done my job. But if they continue to have seizures or they have adverse drug reactions, then you start getting into a little bit more possible need of other supportive things, which is outside the realm of dyslexia, like a VNS or DBS, or sometimes adding on more antiapoleptic agents, unfortunately. So that's the approach. Now that leads to the question that, okay, how do we kind of figure out which one's the best fit for the particular type of seizure? That's a great question. So focal seizures oftentimes respond very well to carbamazepine. And I've become very fond of this next one, oxcarbazepine. I really like this. I've had patients who have many, many focal seizures through the one oxcarbazepine, and it just shut the seizures down really, really well. Another one is levatorazetam or lamotrigine. You can consider other drugs, things like phenobarbital is also kind of a beneficial one, especially in neonates. Remember, phenobabital. The next thing is generalized tonic-clonic seizures. So if a patient develops a generalized tonic-clonic seizure, valproate tends to be one of those first line drugs, as well as levatorazetam, lamotrigine, topiramate, you can consider even phenitone or phosphenitone as well. And again, phenobarbital, remember, phenobabital, it's good in neonates and tonic-clonic seizures. There was one time I did have a really, really bad myoclonic patient. They took on about 150 wellbutrin, and they ended up having associated wellbutrin toxicity and ended up seizing and seizing and seizing and developed myoclonus. And oftentimes when a patient develops myoclonic seizures, the drugs that I found to be the most effective and also evident supports this is valproate, levatorazetam, and then you can also consider things like lamotrigine, but benzodiazepines are also very, very effective as well. So benzodiazepines, again, valproate, levatorazetam and lamotrigine are very effective drugs. The next thing is the absinthe seizure. So if a patient develops a generalized absinthe seizure, it's important to remember this one. That's always the one that you're going to see on the exam is ethosoxamide. Ethosoxamide is usually that first line agent. Alternatives or other ones that are just as good is valproate or lamotrigine as well. So you can consider those. The next thing is what Rob talked about. What I see more often is something called status epilepticus. And so you can see this in patients who have focal seizures that secondarily generalize. In other words, they start off with a focal twitching of the left arm and then all of a sudden over time they lose consciousness and they start moving everything. So it's a focal that secondarily generalize to a ton of chronic seizure. And if they do this for more than five minutes or they have a seizure, they stop, they have another seizure, but they don't have a return to baseline in between those two seizures. That's also defined as status epilepticus. In that situation, the first line agent is usually your benzodiazepine. So things like medazolam, diazepam, and larazepam would be first line. If they continue to seize, then what you do is you give them another drug that will actually help to prevent the recurrence or provide a prophylactic stoppage of that seizures in the future. And that's things like phenytoin. Actually, I apologize. Phosphonitone is more preferable of valproate levitarazetam. And I've become quite fond of lechosamide as well. If they continue to seize despite a benzodiazepine and a phosphonitone of valproate levitarazetam or lechosamide as a prophylaxis, then you can move on to infusions to stop the seizures. So then you give things like propofol, ketamine, or medazolam infusions to stop the seizures. And if they still seize despite all of those, then you go to something called barbiturates. And that's usually phenobarbital or a pentobarbital coma. So that's how we would treat that one. And that really covers those. But then quickly, sometimes you may see these on the exam, you may have epileptic spasms. So this includes that benign ralandic, the West syndrome and the Lennox-Gostoe. Benign ralandic responds good to lomotrigine. The West syndrome responds well to vagabatrin. And then the Lennox-Gostoe requires a lot of agents. It's usually refractory. They seize every single day, unfortunately, despite everything you do. But valproate tends to be good. Lomotrigine to pyramid cannabidiol is another good one, and then sometimes felbinate in the refractory cases. But oftentimes these patients usually require a VNS. But really, that covers the approach, Rob, to treating epilepsy with AEDs. There's a ton of AEDs that you're going over here. And with any drug you take, especially if it's multiple, there's a lot of adverse side effects that could occur. So what are some of these adverse drug reactions that occur, Zach, in some of these epileptic drugs? Yeah. So I think the big thing is, and that's really kind of determining which drug you pick. So if a patient comes in and they're having myoclonus, I want to be able to figure out, okay, which one's best? Valproate, levatorazetam, lomotrigine. I got to think about the particular situation, such as their adverse effects. So if I have a patient who's pregnant, I'm probably not going to give them valproate. If I have a patient with a severe renal disease, I'm probably not going to give them levatorazetam. If I have a patient who has some type of problem where they've had SJS in the past, Stevens-Johnson syndrome, I'm probably not going to give them lomotrigine. So it's looking into their history and looking at those things. It also, not only is it important to know the adverse effects, but it also helps you determine which one is the likely best agent with the least amount of side effects. So to kind of cover these, I just really want to hit the big ones, because there is so many of these, and some of them are super rare, and I think they just put them on things just because it was seen one time out of a million people. But it's important to remember the big ones and the things that actually are really serious. So I think cardiac and respiratory depression is a pretty serious thing when you think so. Yeah, I would think so. Yeah. So when a patient's got a low heart rate, they're hypotensive, they're not breathing very much because they're depressed, kind of central nervous system-wise. That's concerning for me. And so that's why I would avoid heavy benzodiazepine use, propofol or barbiturates. The reason why is in those situations, they can cause hypotension, bradycardia, and they can really cause a significant amount of apnea where the patient can't breathe. And so oftentimes, guess what? When patients get a lot of benzodiazepines, they get a lot of barbiturates or propofol, do you think that these patients are breathing on their own? Oftentimes, no. So oftentimes, we have to intubate these patients to do that. And so that's an important thing to remember. The next thing is SJS, so Stevens-Johnson syndrome. This is that really nasty kind of skin rash that occurs all over the body with the, you know, kind of like whenever you kind of blister it up and you kind of rub that blister, it actually causes kind of the positive Nikolsky sign. You can see this disease. And the ones that are actually really, really important to remember, you can remember Ethan Carl Larry. So Ethan Carl Larry can cause SJS. So this is ethosuxomide, carbamazepine, and limotrigine. These are big ones that have been seen to be more common in SJS. The next thing is apatotoxicis. So if a patient has an underlying liver disease where they already have hepatitis or they have cirrhosis or they have some type of underlying fatty liver disease, it might be a good idea to be very, very cautious with these drugs and consider alternative ones such as, you know, in this situation, apatotoxicity, valproate is a big one. Another one is carbamazepine and another one is felbomate. To some mild degree, phosphonatone and phenatone, but really these are the big ones. Valproate, carbamazepine and felbomate can really cause a lot of apatotoxicity. So if a patient has liver dysfunction, maybe consider being very cautious with this and monitoring those levels or trying another agent. Renal dysfunction is another one. Levatorazetam is very heavily renally excreted. So levatorazetam is one of those drugs that a patient has significant renal dysfunction. Consider another alternative agent or really lower the dose of that drug and monitor them. The next thing is CYP450 interaction. What the heck does this mean? This is basically drugs that are getting metabolized by your cytochrome P450 system. They have to go through the system to be metabolized. There are certain antibiotics that can decrease the efficacy of the cytochrome P450 system or increase the efficacy of that cytochrome P450 system. Let me give you a quick example. So you have drugs that are what's called cytochrome P450 inducers. All that means is that they stimulate the life out of the cytochrome P450 system. The cytochrome P450 system then breaks down other drugs very, very rapidly and you end up with very low drug levels. As an example, say a patient's taking warfarin, which is supposed to be a blood thinner, prevents you from clotting. If you take a cytochrome P450 inducer, it's going to rapidly break down warfarin and you'll have low levels of warfarin and you'll develop clots. That's a problem. What drugs can do this? This would be phenytoin, barbiturates like phenobarbital and pentobarbital, and carbamazepine. Then you have drugs that are cytochrome P450 inhibitors. In other words, they inhibit the cytochrome P450 system and they don't break down a particular drug. And so give an example, warfarin. Warfarin gets broken down. If you have a cytochrome P450 inhibitor, it's going to inhibit the cytochrome P450 system. They will not break down the warfarin. If they don't break down the warfarin, warfarin levels will be super therapeutic and now you have risk of bleeding. And that's seen with Valproate. So Valproate would be an example of a cytochrome P450 inhibitor. The last kind of big category here is those drugs that are teratogenic. In other words, they have the ability to cause fetal demise, fetal disorders of some type. And this is really scary. So it's really important to avoid these drugs and patients that are of childbearing age. They're not on contraception or they are pregnant. So this would include Valproate. Please don't do this one. I've seen it once and it's sad because it can cause a lot of folate absorption issues and leads to neural tube defects. Another one is phenytoin and phosphenytoin. This can cause a condition called fetal high-dentone syndrome. And that's another really scary one. And then carbamazepine, especially in the first trimester, is really dangerous just because it can lead to cleft lips and cleft palates as well. So watch out for that one. The last thing here is sometimes on your exams, they're going to ask very specific adverse drug reactions that are always those buzzword things that you want to associate with an antepoleptic. And that includes for Valproate, remember pancreatitis, right? So Valproate, pancreatitis. Carbamazepine, remember S-I-A-D-H. In other words, it causes excessive amounts of A-D-H production. You reabsorb a ton of water across the kidneys and then you drop your sodium. So it can lead to hyponatremia. Phenitone and phosphenitone, they cause them gums to be thick, right? So it can cause gingival hyperplasia, which is a really unfortunate thing. And then the vagabatrin can actually cause vision loss. And then lastly, to pyramids been seen to cause metabolic acidosis, as well as kidney stones into a rare degree glaucoma. So that would really cover all of the specific adverse drug reactions, Rob. All right, awesome. Awesome, Zach. Thank you again for an awesome podcast episode. We're going to just keep trying to do these every week. But again, I think that was really clinically appropriate and applicable for everyone out there. So thank you. Yeah, no problem. And again, I encourage you guys, as Rob said, again, it's hard sometimes with a podcast to be able to visualize some of the things that we're talking about. Obviously, this is meant to be more of a thing that you come by and you listen to whenever maybe you're you're out on a drive to school or you're at the gym or you're just trying to sit back and relax, whatever it may be. I really encourage you guys to grab those notes, grab our illustrations because I really think it'll give sometimes not just the concept of what we're talking about, but it'll put visual representation to what we're talking about here in the podcast. And I think that'll enhance your learning. So definitely check that out. But ninjas, I thank you guys so much for always sticking around, always being so awesome and being just amazing supporters of what we do here at Ninja Nerd. We love you. We thank you. And as always, until next time, you