hey this is Dr busty and we're in our neurology section where we're going to be doing a fa rather focused uh lecture basically doing a drug class review over the anti-convulsants and this lecture needs to be put in the context of seizure management as a whole um I'm not going to cover every single detail about every one of these anticonvulsants but what I am going to try to do is put the uh put it into the framework of the big picture of managing epilepsy in particular uh it is going to be one of the things you'll recognize as we go through this uh discussion is that these drugs have a lot of somewhat confusing um and varying mechanisms of action which make it quite honestly difficult uh for board exams to ask you specific questions um there are some drugs that have definitive known mechanisms that are historically known as well as clinically been validated at some level um and so could be um things that you could be asked um at the same time it helps us to understand that uh why we sometimes use one drug over another or some patients just need additional um drug therapy in order to get their seizures under control uh while many patients maybe up to 60 to 80% of patients can get away with monotherapy uh there are about 20 to 30% of those patients that need dual therapy or even triple therapy uh to get their seizure under control and this is where some of the various mechanisms start to come in and having drugs with multiple um perspectives on the targeting of um epileptic um activity uh can work to solve this patient's um you know medical condition at the same time uh when you listen to other topics that are available on the subject of seizure managements and seizures in general uh one of the things that's important to recognize is that the they have different causes for the seizure activity um you're going to see that in the underlying pathophysiology you have a couple uh systems that are in place that regulate nerve conduction and I'd like to just give a brief comment about that an overview simply to put the context of the mechanisms of these drugs at their at some level back in tying it into the context of the pathophysiology nerves um conduct basically action potentials up and down them right i mean that's how it transmits information from you know one neuron to another in the in the central nervous system uh there are electrolytes that help propagate those action potentials um predominantly uh sodium um and calcium on the outside um there's also potassium um which tends to be a little bit more on the inside but there's some also available on the outside and typically when a nerve gets activated it typically the action potential is propagated by a rapid influx of sodium which is a positively charged um cation uh and what happens is is that it changes the inside of the cell which is normally at a resting net negative charge okay usually somewhere around you know 50 or 60 to 80 negative 60 to 80 um in its mills um and when those positive charges come in it makes it less negative and more positive and once it hits a threshold of about -40 uh that changes the permeability where the action potential just fires down that um nerve and so as a result of uh sodium influx um propagating nerve conduction uh we have drugs that inhibit that process now once a nerve action potential has occurred uh the nerve undergoes a state of sort of being refractory so after a depolarization of the nerve there's a refractory state where it really can't uh take on another action potential and some of our medications are trying to modulate that period of time before it can take on another action potential so if you can think about an a seizure where we have a rapid recurring seizure activity down a nerve axon this would be a way to help block that process no different than in a heart when we have ventricular tacocardia vib we're trying to prevent that reentrant um cycle from occurring inside the heart through nerve conduction pathways same thing we try to change the refractory period um so the concepts apply and are similar now there also chloride um ions also present on the outside of the nerve cells and they are negatively charged they're annions and so we have drugs that affect the movement of those so if we increase the movement of chloride ions inside of the cell we're going to make it more net negative and the more net negative you make the inside of the cell the harder it is going to be to get it to that threshold of -40 to have the action potential actually propagate and this is where things like benzoazipines work and GABA it helps us to hyperpolarize the nerve so that it's more resistant to action potential so we may then make the inside of the cell and the nerve more net negative um GABA is another we have a number of different neurotransmitters in our brain we have GABA we have glutamate we have norepinephrine we have serotonin right there's a lot of things that modulate transmission of different communication pathways throughout the brain glutam uh glutamate tends to be one of our neuroexitatory neurotransmitters and what I mean by it being an excitatory neurotransmitter it is going to stimulate turn on propagate and so we have some drugs that block glutamate activity or block receptors like at the NMDA receptor by preventing uh an AMPA receptors by blocking glutamates excitatory activity because obviously too much excitatory activity can be part of the problem that's propagating in the seizure itself on top of that we have GABA which is our major inhibitory neurotransmitter and what I mean by inhibitory it it suppresses the central nervous system it makes it harder to receive action potentials and that's what traditionally drugs like benzodazzipines work on now we're going to not focus on uh benzoazipines in this specific lecture there's another lecture available for that topic but uh it is part of our anticonvulsant drug therapy but we're going to be talking today traditionally about drugs that predominantly are considered anti-convulsants in their pure sense now uh GABA which is going to open up GABA channels which traditionally hyperpolarizes the neuron now GABA being the inhibitory neurotransmitter is a good thing in the context of a seizure obviously it's going to slow down and reduce the propagation of that seizure activity by making the neuron more hyperpolarized more resistant to receiving an action potential but GABA also gets then metabolized and there's transaminases that metabolize GABA gaba that some of our drugs that we're going to talk about block and so if we block the metabolism of GABA therefore it sticks around a lot longer if we give drugs that modulate the activity like benzodazipines it allows GABA to work more efficient we have drugs like we're going to talk about gabapentin and pregablin that are basically GABA analoges they structurally look like it now unfortunately they don't work like GABA um 100% but they are structurally formulated to be similar in their structure the point being is we typically target um you know sodium we affect chloride we affect neurotransmitters we also then also affect the release of those neurotransmitters and one of the key chemicals or cations that's necessary for uh release of neurotransmitters from the vesicles of a neuron is calcium so we even have drugs that block calcium channels uh we have calcium influx uh things that can be impact calcium influx and you're going to see that those some of our drugs work in multiple of those pathways the point being before I get started is I wanted to let you know that I fully appreciate and recognize that these medications are complicated they have multiple mechanisms on some occasions and it is sometimes difficult to fully wrap your mind around i will try to point out to you those drugs that are more clinically relevant and more likely to show up on boards key points about those drugs and so some drugs will move through a little bit faster simply due to the fact that they are just what they are and you just kind of unfortunately need to memorize or recognize that that's the issue with that medicine okay um and so if I move through some faster than others it's not that I'm brushing it off as irrelevant it's just that it's just another drug and you'll see that the adjunct therapies for seizure management which are outside of the traditional older agents like phenotin carbomasopene valproic acid and pheninoarbatl those those are the older drugs that are historically used and still used in practice but all these newer agents that many times we're using them now off label or outside of other conditions like migraine prophylaxis or neuropathy or um trigeminal neuralgia or mood disorders such as bipolar disorder and we're not only using them for seizures and so that can muddy up the water and make it a little bit more complicated but that's my goal is to try to highlight some of those because there's just so many of these drugs that are now on the market and some that are coming through the uh development that we're going to probably see again in the future um because again there's money to be made in other conditions other than seizures but as it relates to epilepsy these are some of the drugs that we would use in combination or as monotherapy for the control of those seizures now the last thing that I want to say before I jump into this is that it is important to recognize indications because some drugs and anti-vulsants can worsen some other seizures as a result of using so that is again why we have a nice bag full of drugs that we can use because not all seizures are the same okay and that's a separate topic separate lecture but not all seizures are the same and they don't all respond appropriately so for example phenotin and carbomasopene right they worsen absants or petite maul seizures whereas they're really good for tonicclonic generalized or more complex seizures right so that's really relevant ethosomide is going to be very useful for absant seizures especially typical you know pure absant seizures you know so those are just some of the things that you just need to know and important to differentiate and I will highlight those as it relates to the indication those would be things to star and highlight okay having giving you a little bit of background making sure that we're all on the same page uh laying a little bit of the groundwork as far as footnotes right because this is complicated uh let's get started and we'll kind of go through these drugs one by one now we're going to start off with the older agents which tend to be more clinically relevant because we do use all of these agents many studies that go head-to-head will compare head-to-head with these drugs that have been around a long time unfortunately because some of these drugs are older uh and when they came out they were the only thing that we had and so we used what we could use but they do come with a lot of baggage and issues drug monitoring side effects drug interaction issues that are not as common with some of the newer agents although the newer agents have their own little issues they're not near as complicated and usually don't require drug level monitoring uh like some of these medications so these tend to be higher yield on board exams because they're wellknown wellestablished a lot of evidence for them and use animal models and receptor binding kinetics and models and we understand them and we've been teaching this for a long time so these tend to be a little bit more common on exams for that reason um however they do have limitations in their use and I'm going to point some of those out but you can see the long list of some of these newer generation agents right i mean this list is just been growing by the year and some come and go a little bit um but I think and some have restrictions um which I'll point out to you uh but I'm really going to run through some of those a little bit faster mainly due to the fact that they're either patent extensions or they just have one or two little pearls about them and that's really all there is to know all right phenotin probably the most important drug um and the highest yield uh drug in this discussion and lecture okay so I'm going to be spending the majority of my time on this drug compared to other agents for that reason there's literally probably a good 20 to 30 questions that I could ask literally on a test that would be all legitimate to ask you so the first thing is you recognize that we have a lot of different formulations and that's nice especially when we come back to the dosing part because we need it to be used across multiple patient populations so there's oral there's liquids there's IV unfortunately there's no I am and that has to do with its erratic absorption when you administer it IM because of the pH and the way that the drug is formulated i'll come back to that here in a minute and I'll put it in the context of its prod drug phosphenotitoine or cerex which is more more soluble this drug is predominantly used um and reserved for primary generalized and more complex seizures like tonicclonic seizures in particular the traditional seizures that people think about the you know the muscle action the tightening and then the contractions and convulsions that patients go through um it is known to worsen absant seizures carbomasopene is also another one that is known to do that but interestingly phenotin and carbomasopene has similar mechanisms and that they block sodium channels so you'll see here there's a main mechanism of action that I listed and then sometimes underneath I put some of these other reports reported mechanisms and depending on what source of information that you read you will see some variation in these other mechanisms and how these drugs work i think the point that is important to recognize is that there is a main overarching effect and if you do know that nine times out of 10 you're going to be right on and this is probably legitimately more where they're going to ask the question because they have to be able to justify why they're asking a specific question to you on an exam so you see here it says here it blocks those sodium channels remember it's going to those sodium uh catons come in and they change the inside of the cell to become less negative bring it closer to that -40 which basically hits that threshold in the action potential then fires um so it is associated with blocking and decreasing the depolarization of offering overall membrane stability right now it says here prolongs the inactivation so remember I said after that channel has opened and let that sodium come in there is a phase of resistance or period where it's inactive now if we can prolong that inactive period then we make that nerve more resistant to receiving another fire and so if there's a rapid abnormal firing going on then we can shut that down no different than our class one anti-arithmic drugs that we use that also are known to block sodium inward flux in um ventricular meioytes so that we can treat ventricular tacocardia and vib and those kind of things or try to stop that re-entrant cycling from happening because we prolong the effective refractory period now interestingly because these block sodium channels just like class one anti-arithmic drugs you have to be careful you can see cardiac side effects and widening of the QRS um as a result of using these drugs especially if you use them in too high of dose or you use them in the context of a drug like a tricyclic that is present tricyclic antidepressants are known to also inhibit sodium channels and unfortunately when people overdose okay on a triccyclic antidepressant they widen the QRS on the on the ECG just like the phenotin can do to you if you give it at the right dose um and if they widen it too far we we do know is that it also affects calc sodium channels in our brain and it can actually cause seizures so one of the complications in TCA overdose is yes widening of the QRS ventricular tachi dysriythmias that cause they're life-threatening but they also can cause seizures and so if you have any suspicion for an overdose of a triccyclic antidepressant do not okay and they are seizing do not give this patient phenotin phosphenito carbomasopene any of those drugs that are going to block sodium channels because you will worsen worse worsen not only the cardiac conduction but you could potentially worsen the seizure as well uh and I know that sounds counterintuitive but it's integrating knowledge and other topics as it relates to these drugs because you want to use them in the appropriate setting so in any tox okay that any question or related to toxicology if there's seizures the answer is never ever phenotin because of that mechanism okay and what I just explained to you if that didn't make sense to you stop rewind it that is absolutely important if you don't understand anything about anti-arithmics then listen to that topic okay if you have access to that point uh if toxicology same thing with TCAs okay the point is understanding mechanisms helps to understand why we see things in other areas of practice okay all right so I think I said enough about the mechanism i mentioned early on dosage formulations being really helpful with dilantin so we have chewable tablets we have a suspension that makes it more easy for patients to swallow we have capsules that can be used for adults and can be carried around a lot easier and then of course we have injection but only IV administration we don't use phenotin or dilantin in a IM injection and part of the reason has to do with the way it's formulated now propyline glycol is particularly inside of this formulation for injection uh Adavan has the same sort of problem okay when you administer propyline glycol IV and you do it too fast okay iv push too fast all right usually greater than 50 milligrams per minute uh that can cause tacky dishythmias but also uh hypotension but the reason it's formulated this way is that the pH um of this is it's messed up and it's not very water soluble i'm sorry not very soluble when you inject it and what happens is when you inject it into tissue okay like the muscle the pH is different than the pH of the solution and what ends up happening is that changes the pH of that environment and the molecules and the formulation starts to crystallize and precipitate and so because injection causes precipitation okay listed here it changes the absorption and makes it very erratic less predictable something you definitely don't want to rely on in an acute management of a seizure okay so we only give it IV now this is different than the prod drug phosphenitoin or cerbex which I'll mention here in a minute okay well in fact it's right here phosphenottoine or cerbex is the prod drug it is more soluble and can be given IM and that's another important differentiation between drugs is the root of administration so really make sure that you understand these things here now the reason that we also have a number of different strengths and formulations is has to do with the elimination and metabolism of phenotin we'll see here in just a second that initially it starts out what's called first order or linear elimination type of kinetics but then at a certain dose we saturate the elimination pathways and as a result of that it turns into zero order where the levels can then exponentially rise and unfortunately this drug has got a narrow therapeutic index to it and too much drug can cause toxicity and side effects again I'll come back to this in a minute but the point of notating the number of do dosage formulations allows for small incremental changes in the dose because once you get to standard average doses then there's at some point it's going to tip over and go from first order elimination kinetics to zero order and if you don't make dose adjustments that are very small you can not only saturate the system of elimination but then the levels exponentially rise and shoot up because of that zero order elimination so having formulations with a number of different doses and uh dosing strengths helps to facilitate those tweaks that the higher end of the range that you need to do okay so how do we dose this in the more imu emergent and acute like we need to get the drug levels up one of the things that's known about management of seizures is that the levels need to be consistent okay or or as much as possible remain at a certain level in the body too much is not a good not enough can sometimes not be uh not good as well so we want to try to keep this level and so we need to get to that level which is steady state concentration and so there are loading doses that are used we can give that IV which is traditionally what's done or we can do it by mouth uh when you look at the dosing it is uh 20 mg per kilogram on average is the dose now that will take you up to a theoretical level of 20 uh so the normal reference range for this drug is somewhere around 7 and 12 to 10 on the lower end up to 20 once you exceed 20 you start to develop some side effects and then you start to move into the toxicity so if we do 15 to 20 milligrams per kilogram then you sort of hopefully with a loading dose achieve steady state because that's the whole point of a loading dose is to achieve steady state quickly otherwise if you do it starting out at traditional dosing okay which is fine in somebody who's not actively seizing or is in an outpatient otherwise doing okay uh it takes up to a week to reach steady state because of the halflife all right uh so this is how we load uh you do a 30 300 mg at once and then 2 hours later you give another 300 mg this is the way to make it most tolerable there are regimens where people do 600 and then followed by another 600 or 500 and 500 um they to try to make it more tolerable on the GI tract and maximize the overall absorption uh but uh this is obviously this regimen here that I've highlighted which is one way of doing it is going to take a couple hours to obviously do it um the IV load is nice because you can get it over with you just have to make sure that you don't infuse it too fast so the maximum rate of infusion is 50 mg per minute that is different for phosphenotin or cerbex which you can give at 150 milligrams per minute because it doesn't contain the propyline glycol remember you push it too fast in the IV and you get it into the syndrome you could cause hypotension and bradriythmias in these patients and that's why we have the limit and that's important for you to know it's clinically relevant very commonly asked on board exams and is a common side effect or complication of the drug now average doses at least for adults is somewhere around 3 to 400 milligrams once you exceed or approach that dose then you start to get concerned about that switch in the elimination kinetics that I mentioned going from linear or first order elimination kinetics to zero order and nonlinear where those levels can then start to rapidly rise and they can get above the the 20 okay uh and this is where we start making small dose adjustments at that point because remember you don't know for that patient where they're going to hit that saturation point so when you look at the levels this is a plasma concentration that you may have get back after a certain period of time you see that the dosing changes are very small compared so for example let me just say for uh give you an example to make this come put to put it to reality here let's say you're on 300 milligrams a day of dilatant or phenotin and that level comes back at seven okay and you're like well I really want it to be closer to 15 and I'll just give them 600 because if 300 is seven you know then then 600 should be about 14 to 15 no that is incorrect thinking u it it could be that going from 300 to 350 takes them up to 15 you know or 300 to 400 takes them up to 15 so that's where these small adjustments um start to occur now this is a generic rule of thumb for every.74 milligrams per kilo that you give the patient you write raise it by one now again that's only assuming that you haven't hit the saturation point now when do you check levels i mentioned the 10 to 20 some people say 7 and 12 to 10 you know again whatever controls the seizures use the lowest drug uh dose and uh level that's necessary to get the seizure under control uh if you do it without a load okay the halflife of the drug is about 20 hours so it will take about a week in order to achieve steadystate concentrations again that's the whole point of a loading dose is to get there quicker okay now if you give it as phosphenito phosphinitoine gets rapidly converted to phenotin okay so that's what you're going to measure you're not measuring phosphenottoine levels you're measuring phenotin levels now when you do a level like this the 10 to 20 you're measuring everything present in the blood bound and unbound and remember the drug that's unbound or the free fraction is what is pharmacologically active now phenotin carries a high proteinbinding profile that means a lot of it is bound up not very much of it is free or unbound any drug or anything that reduces either the protein binding sites okay like you're not making as much albamin or you displace the drug from binding sites increases the free fraction and increasing the free fraction of a highly proteinbound drug like phenotin can increase the free fraction which increases the pharmacologic effect that the patient is now having to experience as a result of that the patient then can experience side effects that are different and may not be expected remember when you measure the level you're measuring both free and bound drug so there is the ability to measure what is called the free fraction or free phenotin level and that level is one to two and that makes sense because if if it's a highly proteinbound drug very little should be free and you see that it it is so the total is 10 to 20 the free uh or unbound is 1 to two okay and if you're not sure then measure the free because sometimes the total can be misleading as to the clinical picture that you're seeing so for example somebody can look like they have dilin toxicity okay and have a normal lab but it's abnormal because too much of it is free remember it's the free that is pharmacologically active now when you give phosphinitoine IM you have to wait about 4 hours for it to all convert over to dant before you check a level if you give it IV it takes about 2 hours roughly okay all right so here are the different toxic levels right once you go over 20 start to develop nice stagmas start to get into the atexia where they have trouble walking they feel dizzy off almost like they're intoxicated once you get over 30 that taxia starts to go up you can even start to have seizures remember I was telling you earlier you give too much sodium blockade like with tricyclic antidepressants you can cause a seizure uh going over 40 this is where coma and even potentially death life-threatening conditions start to happen where you need to protect the airway as well so when we monitor the drug we not only look at the di the total level but we also look at the albamin and the blood ura nitrogen level and the reason that we look at BUN okay okay is because BUN can create uh uh create a competition for binding sites on proteins and displace more of the drug and make a free fraction there is a phenotin correction formula that you can use um that can calculate the estimated true level in somebody who has low albamin or high uh bun um but uh that's sometimes hard to remember and I don't know that board exams are going to ask you to calculate that okay so that's when you would then measure just the free dilatantin level now there are a number of side effects so you're suppressing the central nervous system so you can get sedation um in CNS depression that's sort of true for a lot of these drugs um but some classic side effects that you will see on board exams and in real world practice is gingal hyperplasia now there are two other drugs that also do this calcium channel blockers have been associated with it as well as cycllosporin one of our imosuppressive drugs for transplant patients uh so gingal hyperplasia um is one of those things heretism which is facial hair and coarse facial features right hypoglycemia plus or minus hematic effects yes the osteoporosis concern has to do with reductions in vitamin D uh one of the problems with phenotin is that it's also known to cause drug drug interactions why because it's an increases cytochrome P450 3A4 activity and so it can metabolize things off and one of the things that it lowers is not only vitamin D but um also drugs that are substrates of 3A4 now it is associated with uh rashes and unfortunately um they can on occasion be life-threatening um one of them is a system a syndrome called dress which is drug reaction with eocinophil um eocinophils that are high and eocinophils tend to show up with drug allergies and reactions and a skin rash that occurs it's and it's a syndrome um so it's affecting multiple systems uh but one of them is that they get a skin uh rash is associated with and that's known as dress the megaloblastic anemia comes from red reductions in folate and so they get like a B12 folic acid looking deficiency so they have a macroitic uh red blood cell instead of being by concave um like all anticonvulsants they're for the most part all considered some have different types of strategenicities over others but this one in particular is problematic because it is associated with fetal headtoone syndrome and again when you have syndrome you have multiple things happening in the body so they can develop cleft pallets congenital heart disease and then mental impairment uh that can be obviously permanent in nature so you know we we want to minimize the exposure the unfortunate problem with managing uh seizures in somebody who is pregnant is that pregnancy increases the seizures and makes it more difficult to manage woo it's a lot for phenotin right like I told you 20 30 questions I could ask you about that now we'll start to move on a little bit faster because some of the other drugs don't have near as many issues uh with them but we store in some of our older drugs so these are important and carbomasopene is another very very still commonly used anticvulsant for a number of indications we have a number of different marketed brand versions some of them are specific to a you know an indication but for the most part uh this is historically known as an adjunct to partially controlled or secondary generalized tonicclonics seizures but like I said with phenotin it can worsen absant seizures or even myoclonic seizures and so we want to avoid their use in those situations and that's another important pearl that you should highlight this is the drug of choice for trigeminal neuralgia uh which is a basically a type of neuropathy the trigeminal nerve is a very large nerve in the head um and intervates a lot of different parts of the u of the of the um face and head and so it's very important uh causes a lot of excruciating pain but it is a type of neuropathy and the reason this is you know if you think about nerve pains nerve problems if we block nerve conduction theoretically it makes sense uh we also use it as a mood stabilizer um for bipolar disorder and it's one of our standards of treatment so you have valproic acid carbomasopene lithium which have been around a long time we also use another anticvulsant which we'll talk about here in a minute lamotrogene or also known as lameal uh it is also used for mood stabilizing effects for bipolar disorder so how does it work well it blocks those sodium channels very much just think of it like phenotin okay now you'll see here again these other sort of mechanisms and points i'll talk about trilpto here in a second some people thinks that oxarbazopene or trilpto is a metabolite of carbomasopene and that's just not the case it's a separate drug but the the thing up here about working on this adenosine alpha 2 A and B receptors this has to do again with some of these other modulating activities as it relates to either calcium and some glutamate activity um and stuff like that and again because remember there's no multiple nerve regulatory systems we're trying to create a balance to reducing the expression of things that would facilitate seizure activity now carbomasopene and if you think about the trigeminal neuralgia the neuropathy it has a similar structure to a triccyclic antidepressant I'll show you that here in a minute but we use triccyclic antidepressants in lowd dose for neuropathic pain so it makes sense in some level not only by its mechanism of sodium channel blockade but also its effects on neuropathy that it would be used as a drug of choice for trigeminal neuralgia now if you think about pain syndromes right and triccyclic antidepressants inhibiting sodium channels again it's affecting nerve conduction so any drug that really affects nerve conduction has the ability to probably work on nerve related pain syndromes and that's one of the reasons why triccyclic and even triccyclic like drugs uh things like um symbalta duloxitine for example venlaxine desenlaxine these drugs are also used for neuropathic pain syndromes um and that just sort of hopefully makes sense so if you look at carbomasopene which is right here you see that classic triccyclic structure now if you look over here amipramine is one of your triccyclic TCAs right that so you structurally it looks very similar and as a result of that um that's one of the reasons why amipramine probably works for neuropathic pain and why carbomasopene is the drug of choice for trigeminal neuralgia now when you compare it to oxcarbasipene it looks very similar but you can see right here in particular this is one of our main differences it is not a metabolite so trileptal is its own drug it stands by itself it's just related to um structural similarities to carbomasopene we'll talk about its advantage here in just a second um but I wanted to point that out because some people misunderstand that now carvomasopene gets metabolized predominantly through phase 1 metabolic pathways 3A4 similar to uh what can happen with phenotin and so one of the problems with this is that it it does form a metabolite that's important for part of its mechanism but unfortunately it also causes problems uh that metabolite the 1011 epoxide metabolite um induces now back onto these enzymes and what that means is that it turns on the 3A4 enzymes and makes more of them so now that we can start to more rapidly metabolize this drug as well as any other substrate of 3A4 so just like with phenotin it is associated with drug drug interactions but because it's such an enzyme inducer in it induces its own metabolism and as a result you have to increase the doses over time and so when you look at the dosing you start out at 200 milligrams here for example an adult twice a day for 3 days and then you have to increase it to three times a day because the the drug is inducing its own metabolism and so you have to bump up the dose and then you start to measure the levels um and 4 to 12 is historically known as the reference range for this again sort of has a narrow therapeutic index to it but this is the the window of efficacy for seizures in particular um so you need to memorize any drug that comes with a reference range that's really important for a board exam so you saw that with phenotin you're going to see you see it with this you'll see it with valproic acid as well um the um unfortunately there's no IV formulation and this is one of the reasons why we don't use it in conditions like status epilepticus or even post uh seizures uh than patients who are still post-dictal because they have to would have to swallow it by mouth um so it is metabolized by the via phase one the metabolite then induces itself and so the autoinduction reaches its maximum about two weeks so you may have to dose adjust the drug up further this can then lead to drug drug interactions with a number of different medications this is not the complete list it is just an example of those that sometimes show up on boards all right um but it is important to recognize that phenotin uh carbomasopene phenibarbatital primadone uh these are enzyme inducing drugs that cause clinically relevant drug drug interactions there are any convulsants that other cause drug interactions but they're not from so much inductions of the cytochrome P450 system uh just like with uh dilantin or phenotin uh we have pregnancy category D but it's not fetal hedantoine syndrome um these patients uh can just develop a number of different tradenetic effects and so this is just similar across the class you're going to see that pretty much all the way through these drugs now this is probably one of the biggest and most important points of the side effects that you should memorize and know there are a lot of other side effects of carbomasopene i'll briefly mention here in a minute but this one is life-threatening and is concerning patients with known genetic polymorphism to HLA B1502 and I would memorize that i think that's really important to know because it's been around long enough now that we know that it's an issue but it's associated with Steven Johnson syndrome and toxic epidermal necrolysis what makes them different is the degree of distribution and how much the body is is hit by it but the point of both of these uh these are life-threatening skin reactions that where patients need to be admitted to the burn ICU and so they're treated just like patients with significant second and third degree burns and unfortunately there's not a lot of treatment other than removing the offending agent plus or minus steroids maybe uh though that's questionable in its benefit um but it carries a fairly significant life-threatening effect and can also even affect the eyes um and so when you see this you'll never forget it and uh if you've ever worked in a burn ICU or burn institution that receives transfers from patients from other institutions this is devastating disease um so we see it obviously with sophonomide allergies but there's a lot of drugs that can do it dress from phenotin can also be associated with it so you really really have to be careful with it but carbomasopene HLA B1502 memorize it know it star it you know I'm doing back flips standing on my head spinning around you know whatever blinking lights whatever helps you uh really important now it is associated with small degree and these are the a lot of these side effects that I list these drugs and other this one and this other drugs many of these are just they're rare but they show up and they can be relevant um and so it's important to keep in the back of the mind so bone marrow suppression um it has a blackbox warning for causing ausing a granuloscytosis and alastic anemia so a significant bone marrow suppression can occur especially if you're co-administering it with other bone marrow suppressing drugs things like zyavodine or at which is an HIV medication we obviously have a lot of chemotherapeutic agents we have drugs that suppress the immune system that can do the same thing so obviously co-administering medications that are known to do that can facilitate that bone marrow suppressing effect hyponetriia we tends to release antidiuretic hormone so it creates a state of SADH syndrome of inappropriate antidiuretic hormone this causes a uimmic hyponetriia kind of picture uh drowsiness fatigue makes sense because it's a sodium channel blockade no different than phenotin all right so as I mentioned oxarbazopene is not a metabolite of carbomasopene it is its own standalone drug it's known as trileptal available tablets and suspension note it does contain alcohol and this may be very relevant if someone is also needing to take metroniditool or known as flagagile because of the dulfuram like reaction or if they're on dulfuram uh which is antabuse for patients who have chronic alcohol problems uh then this cause significant nausea and vomiting if you administer this drug which contains the alcohol now there's another uh liquid formulation of a drug that has a lot of alcohol and that is known as linen ritonir which is a solution for the treatment of HIV 42% of that drug formulation is alcohol so it's important to know these things because they can cause adverse effects in other drugs that sometimes clinicians aren't paying attention to because they don't know that it can happen so that's really really important to recognize this is an adjunct like a lot of the newer agents to partial seizures um it's not approved for bipolar disorder but it can be used as a replacement is there a cross reactivity to allergies between carbomasopene and oxcarbasopene there are cases of it and so you probably do want to avoid it so while it's structurally similar it is not a metabolite okay but it does work on those sodium channels it may modulate the activity of those of the calcium channels and remember as I said at the beginning calcium is necessary for the release and the fusion of a vesicle that's containing a neurotransmitter to release that uh neurotransmitter into the synaptic cleft um you'll see here that it it while it this is the big difference between oxarbazopene and carbomasopene car oxarbazopene does not uh is not metabolized by 34 under instead it under goes a different type of reaction but it can still induce enzymes and that's one of the reasons why you will still need to dose up the drug okay um so just keep that in mind also if you're the um immediate release formulation can be taken without regard to food but if they're on the um extended release formulation then they should take it on an empty stomach and that's an important counseling point for these patients to maximize remember keeping the levels consistent um and so whatever that is now there is no drug level monitoring uh for this but you do have drug drug interaction so here's the carbomasopene effect that forms that 10 1011 epoxide metabolite that I mentioned u but you see that oxarbazopene and this is that epoxide we don't see that forming here um and it does not go through the cytochrome p450 however it still increases the risk of drug drug interactions this metabolite does um and so you can still see that okay so still pregnancy related issues juice maybe not as bad although it hasn't been around as long um while there's a little bit less side effects with oxcarbasipene probably because of that metabolite um that does not mean that the allergic reactions are zero now it does not have the same um HLA B1502 genetic polymorphism concern at the same time as I mentioned there have been case reports of people switch from carbomasopene to oxarbazopene and having adverse drug events associated with it um overall fairly well tolerated doesn't have near the blackbox warnings and concerns it's mostly things like dizziness fatigue you know if blurred vision same things that anywhere CNS depressant type of activity can um uh you know occur now esarbaz carbazine uh this is a newer med medication for just partial onset seizures it's again adjunct therapy no one knows exactly the mechanisms but it thought to block sodium channels just like ox carbazopene just like carbomasopene uh there is no IV option so it's only available really for outpatient use uh halflife is about 20 hours similar to that of phenotin I just put in here the differences and the structures that you can see up you know up here there's very sim a lot of similarities but where it differs is predominantly right here so it's a major substrate of 2B4 which is not a common pathway thankfully for drug drug interactions um but it can still induce 3A4 uh through uh and rec drug interactions of substrates of 3A4 and so that would be somewhat relevant inhibiting 2C19 can be somewhat concerning especially if someone's on a drug like clitigril or known as plavix because that is one of the met metabolic pathways for its activation so that it can work as an anti-platlet um drug so I kind of already mentioned this uh side effects dizziness drowsiness same sort of things as oxarbazopene nothing really magical here i just wanted to include it since it's you know a newer agent within the group that looks similar now valproic acid uh this has been around a long time kind of like um carbomasopene has a number of different mechanisms of action i'm sorry uh indications we use it yes for seizures including complex partial seizures status epilepticus because this one is available in an IV formulation although we don't traditionally use it for status epilepticus you can uh based on previous and historical use um it is a drug of choice or an alternative uh for absant seizures so if you don't have access to ethosomide or there's some contrindication to using ethosomide then this would be an alternative option uh bipolar disorder uh it's one of our mood stabilizing agents so carbomasopene valproic acid lithium classically are those uh mood stabilizers now all all the antiscychotics for the most part are and of course lamedal um we also use it for migraine treatments in acute migraine so for abortive therapy we give it pretty rapidly about a gram over about 10 minutes uh but we can also use it for migraine prophylaxis okay migraine prophylaxis so for prevention of migraine so that's an important one we'll see here in a minute topyramate or topamax is also used probably more commonly than valproic acid for migraine prophylaxis but those other indications are very important to recognize and I hope that you're seeing that trend as I cover these drugs now valproic acid comes in a number of different formulations we have valproic acid which is your depen historically depaote is basically an intericcoated formulation that's more uh tolerable because one of the big side effects of this drug is GI side effects but the intericcoated formulation is more uh preferred by patients and well more wellreceived but once it gets in the body it doesn't matter where it came from uh valproate sodium it turns into valproic acid in the body it's all handled the same it doesn't matter what use depote okay now how does it work well it does partially block sodium channels similar to carbomasopene and similar to phenotin but it may also increase GABA remember GABA is our major inhibitory neurotransmitter by inhibiting the degradation so it blocks that GABA transaminase enzyme that would normally metabolize GABA and take it away so by blocking the enzyme GABA levels stay around a lot longer and GABA facilitates the opening of the GABA channel that allows calc uh chloride to move in and that makes the inside of the neuron more negative okay and again more negative making it -90 for example means it has to go further more positive to get to that -40 threshold that's on average where the action potential then fires down that nerve there is thoughts that it might also influence uh gl glutamic acid decarboxilase but again that's not going to be a test question if they focus on anything it's going to be the sodium and the GABA in uh metabolism inhibition all right um so this is started out at low doses traditionally titrated up usually divided in two to three divided doses for tolerability issues uh there are different formulations including extended release formulations that sometimes don't get fully absorbed and so they need higher doses if you end up switching somebody to doing that as I mentioned there is an IV formulation that can be used for uh acute abortive treatments of migraine headaches but theoretically could also use status post you know status epilepticus uh usually we use uh benzoazipene like dasopam laorazzipam or mazzylam to get status epilepticus under control usually um and then we start them on an anic convulsant afterwards so this can be given to somebody who has trouble swallowing or who has an altered mental status like in a post-dictal state that sometimes happens post seizure now I have read and have seen different ranges for the drug depending on what source you look at uh people will say somewhere between 50 and 100 i've seen it go all up to 150 on some cases and some clinicians and experts in neurology say that they dose it based on the response uh you just need to recognize that once you exceed 150 that's where the reported side effects really starts to take place so I don't know where if a board exam depending on the writers bias their perception I don't think it's a fair test question personally but I give you that little caveat now this drug is metabolized predominantly through phase 2 and unfortunately it's known to inhibit UGT enzyme which is part of our phase 2 metabolic pathways for drug metabolism so there are drug interactions and one of the ones that is of greatest concern is lamedal or lamotrogene now remember valproic acid is a mood stabilizer for bipolar and so is lamed so you have to be very careful about co-administering these drugs because valproic acid inhibits the metabolism of lamotrogene you're like so what who cares well it does matter because unfortunately uh lamed is associated with a dose or concentration dependent effect on risk of of skin reactions and Steven Johnson's being one of those and so when you're dose dosing somebody on lamedal you have to dose titrate this drug slowly um and we tend to see it uh occur early on especially if somebody's getting it too quickly now it is like other um anticonvulsants pregnancy category D causes neural tube defects like I said before at the beginning GI side effects are the number one problem with the drug and that's where um the entic formula entic coated formulation that I talked about was preferred by most patients to help reduce some of that they get nausea and disyspsia and they can vomit the other problems that you see listed here include weight gain which actually shows up a lot on some of these patients especially with bipolar uh there is small risk of liver toxicity so monitoring a alt occasionally in these patients there have been case reports of pancreatitis uh thrombocytoenia this can show up especially at higher levels um and patients needing to go to surgery should have a CBC checked to make sure that that hasn't developed teratogenicity mainly because of folate deficiency similar to what we see with um phenotin and then this one's another one you want to star hyperamineia um and this affects um so when you break down amino acids the amine group goes through the ura cycle in the liver and that forms blood ura nitrogen okay so bloodia nitrogen is the end product the more water soluble product end product of ammonium um which is the aman group from the amino acid uh when you don't have you have a disruption of the ura cycle you can accumulate the ammonia or the aman groups and that then causes an encphylphopathy similar to what we see with serotic patients who have no synthetic function so they can't metabolize these amines and ammonia to blood ura nitrogen and so as a result it accumulates if that happens one of the treatments or antidotes is LC carnitine or carnotaur okay this is really important okay i've seen levels of ammonia go up to 300 in patients on valproic acid and can come in pretty symptomatic and so when the level is over 100 then you definitely want to start to treat them with Lcarnitine therapy and I put those doses down here for you um at the bottom all right um so ethosomide is only used for pure absant seizures now there is an atypical absant seizures usually they last longer absant seizures are these short little periods of usually blank stairs like some of you probably have right now staring at your computer uh right but they're these short periods of blank stairs so it's a it's unfortunately a complex seizure because it changes the um mental status of the patient um because there's a period of nothing and then they just move on like nothing ever happened they don't even know that there was a period of silence u so they have these blank stairs atypical absant seizures we do not use ethosomide in those patients um and uh they just tend to be longer periods and usually from something else now um as I mentioned remember there's all these different mechanisms that's going on regulating neurotransmitters nerve conduction well this one primarily blocks Type calcium channels now there's other types of calcium regulatory channels uh but this is the T type and remember calcium is necessary in order for those neuro those neurotransmitters and the vesicles to merge with the cell membrane and be released now it does have some of these other mechanisms but this is the key mechanism um that is here uh and may influence these you know why it works specifically on absant seizures but that's really only its um main thing uh its use uh the reference range is somewhere between uh 600 60 and 100 there have a couple sources that go up to 125 uh fairly well tolerated the biggest issue is rash uh lucopenia so you have to check periodic CBC's there have been cases of lupus-like syndrome but you know so that's it that's all you need to know about this drug so pheninobatl been around again a long time it is a uh alternative to generalized tonic clonic seizures uh we don't generally use it first line because it's pretty sedating uh I think that's the number one complaint with this drug um but it can worsen absant seizures as well so think of phenotin carzopene pheninoarbatl can all worsen absson seizures we just avoid them that's remember there's only a couple drugs for u for that and you again should focus on the other lectures that talk about seizure management because that's not truly what I'm trying to do here uh so this enhances GABA mediated inhibition so what think of it like a benzoazipene um but it works by opening these GABA channels directly itself but then it also allows GABA which is the major inhibitory neurotransmitter to work more effectively and as a result we open it more and those cal the chloride channels keep opening opening opening opening and it keeps pushing that in there and it hyperpolarizes the neuron now it may also decrease glutamate remember glutamate is the major excitatory neurotransmitter and it works on ampa receptors so remember if we block the NMDA or the ampa receptors we block glutamates activity which is excitatory and is potentially problematic it may also at higher concentrations block calcium uh channels as well okay so multiffactorial uh this is looking at the GABA receptor and this is just showing you these chloride ions on the outside of the cell and when they come inside of the cell it makes it more hyperpolarized you know again remember the range is somewhere between 60 and80 so it can push it up to negative you know depending on where you're at it just makes it more negative on the inside and as a result of doing that uh it facilitates uh the hyperpolarization and now there's other drugs so I show you here this is what a benzoazipene does it works on a different subunit valyan root and cava also which are herbal medicinals also work on the GABA channel and which is why they have anti-anx anxolytic activity why it's used for insomnia it can also cause seen depression you don't want to co-administer these um herbal medicinals in patients on benzo or pheninoarbatital for this reason so when you look at uh phenobarbatital being barbituate it not only opens the channel like I said by itself which is different from a benzo see here's benzo that means as a result of not only doing what a benzoazipene does to GABA but it also opens that channel that the pharmacologic effect is much greater uh and so that's where the CNS depression and sedation really starts to kick in okay all right now with bzzoazipines okay uh if you tend to take higher doses you're probably not going to develop respiratory depression um and the risk of sedation and hypnosis and all that is a dose so as you move across here the doses increasing concentrations in the body are increasing to exert the pharmacologic effect here but when you look at barb barbituates you can see that we start to get all of these things around the same dose remember that has to do with the uh additional mechanism of binding to the GABA channel itself regardless of the presence of GABA and it works and so you can see a lot more sedation some hypnosis and amnestic effects that occur sometimes with this which is why it's used second line but it's very effective um at treating those conditions now unfortunately like phenotin it causes a lot of drug drug interactions it's a strong enzyme inducing agent okay um as I mentioned the main side effect is sedation the desired uh reference range you do need to monitor the levels is somewhere around 15 to 40 and when you go above 50 uh that's when you start to really start to see the respiratory depression issues and concerns popping up now primadone primadone is metabolized to two end points one is puma the other is fenibarb so it c it treats both now this is nice because it can be used as an outpatient um and and management but it uh but you also need to monitor levels so you monitor levels of the puma and then you obviously need to monitor levels of phenobarb itself and it can cause drug drug interactions just like pheninoarbatital can for obvious reasons now with renal impairment you got to be careful because some of these metabolites can start to accumulate and then start to cause more um sedation it obviously induces just because like just like phenobarbital does so you can start to see the CNS depression the sedation side effects those types of thing make sort of sense the megaloblastic anemia comes from the reductions in folic acid mainly from the induction properties that metabolize these um vitamins off um into you know make the concentrations a little bit uh lower okay uh so I'm going to pause here uh so that we break these up um and we'll finish up the other sort of newer agents um in the second or part two