this is Dr Busty and we're in neurology uh section where we're going to be finishing part two of a review over um anticvulsants And if you uh haven't watched part one I think it's important to stop here and start with part one first u because I give some background information and lay some you know discussion foundation for the understanding mechanisms of action And this last part here is really going to be a little bit faster than uh the other section mainly because these are uh newer adjuncts Some of them are used not even so much more um for seizures They're used off label and other or for other indications that I'll point out to you Um and they have very focused kind of small things So this is going to be a little bit more straightforward uh less high yield although there'll be highlights that you should pay attention to So lamotrogene or lamed has been around for a while Uh it uh is an adjunct for partial and or epilepsy that's refractory to other agents but it's also used as a mood stabilizer in the treatment of um bipolar disorder It is also one of our drugs that we would use for lenovo gastat syndrome which is basically a combination of absant seizures with myoclonic seizures It seems to be a variant of that Um and we know that uh absant seizures have very specific drugs that are only used in that situation Some drugs can worsen it Uh leno gastat is basically combination of seizures that are h types of seizures that are happening Um so we don't have an IV formulation Um many of these products come and go but uh sometimes they have available um ODT although it's more expensive This may be helpful for especially kids uh with significant mental impairment uh that may uh have difficulty swallowing pills and so this can be helpful in that scenario So as you remember from the mechanisms discussion sodium inward movement would make the inside of the nerve more positive and less negative to reach that threshold of around -40 which then propagates the action potentials through the nerve And so it's blocking sodium channels but it may also influence calcium channels that facilitate the release of neurotransmitters from their vesicles and the nerve endings So multiple indications also including bipolar disorder and length syndrome and then mechanism uh is multiffactorial uh in nature Which one they pick on I don't know Uh we do want to start out and this is really important This is a testable uh thing about the dosing and it's key uh that we start out at a low dose and you titrate slow um to reduce the side effect potential And one of the side effects that we're most concerned about is the skin rash that can occur including the development of Steven Johnson syndrome which is a life-threatening dermatologic reaction that occurs uh if it happens it's usually in that first to six to eight weeks when that dose escalation is occurring um and or in the um with the use of another drug like valproic acid which inhibits the metabolism of lamotrogene and elevates those levels So one of the problems with lammoagene is it is a substrate of phase 2 metabolic pathway UGT1A 1 A4 and 2B7 and unfortunately as I mentioned valproate um can inhibit uh that pathway and that can certainly exacerbate the uh reaction So this is an example of showing that valproic acid inhibits 2B7 mediated metabolism that would then elevate the concentrations of the modrogene and therefore then increase the risk of the uh skin uh rash Okay Um and so that's key um that is a very very important drug interaction tends to be higher yield Now gabapentin and I'm going to kind of talk about pregabalin in which is lica in the context of this uh because they were developed to be analoges of the structure of GABA essentially So if you remember GABAS are major inhibitory neurotransmitter despite being um analoges are structurally similar to GABA They don't work like GABA Um so I know that sounds kind of backwards but it just doesn't Um in fact the way that these drugs work is that they uh bind to this particular subunit of the calcium gated channels um affecting g calcium mediated release of neurotransmitters um in the synaptic cleft Now it may um also elevate a little bit of the of GABA levels in the pre in the blood but or in the brain but again this is not its primary uh main effect Uh so Neurotin is historically the drug or marketing brand uh form of choice There are other options that are out there Um we also use these probably more off label than their partial seizures and that includes poster uh herpatic neuralgia So patients who um basically have developed you know shingles and they now have nerve damage from the shingles that they develop So post-urperatic neuralgia diabetic neuropathy post-operative pain restless leg syndrome hot flashes and it's even being used for fibromyalgia Um although it's not indicated here Now the dose titration is really based on in part side effects The maximum um dose is somewhere in this range for most patients but most people really get the benefit probably closer into that 2,000 mgram range The unfortunate problem is that it's highly dependent on renal elimination just like pregablin And so you need to dose adjust it um and re uh consider dose reductions in patients with impaired renal function whether it's acute or chronic Um and that is probably the number one problem because sedation and fatigue as it's number one issue Um and so that's worse in patients who obviously accumulate it No drug interactions that are of clinical relevance at the level of the cytochrome P450 system Drug interactions that cause sedation that's another thing Okay Now pregablin or lica again is uh used for neuropathic pains post-urperatic neuralg fibromyalgia uh and sometimes patients in some formularies uh will uh require patients try gabapentin before and fail that before they try pregablin Um but the mechanism is the same as gabapentin The thing that makes it different is the strength So it's it's about three times more potent uh than um gabapentin is And potency doesn't mean it's better It just means I have to give less of the drug to exert the same pharmacologic effect And so when you look at the differences in the max doses that's reflective of that difference in potency So you know while the average maximum dose is around 33 3,00 to 3600 milligrams a day uh with gabapentin it's 600 milligrams a day uh with pregablin so a big big difference um again like I said with gabapentin highly dependent on renal elimination and that's that's a key part of the thing about pharmacocinetics and dynamics that's one of those things that you should know um but and then sedation is still key here um as a problem All right So like I said we're just kind of moving through these other ones There's a long list of them So I'm just going to point out the highlights especially as we move through some of these less common used agents So felamade or phalatl is reserved pretty much for lenovast syndrome It antagonizes the NMDA receptor So remember glutamate uh which is the uh major in excitatory neurotransmitter will bind to and interact with the NMDA receptor U there may also be a small amount of involvement of antagonizing the sodium channels So again multiffactorial but this one um glutamates uh inhibition of activity is probably one of the more common sited Unfortunately it is associated with a bone marrow effect um called alastic anemia that tends to occur usually in the first couple months of use and that's its main primary limitation Uh tiagene uh again indication here partial seizures just like a lot of these drugs uh now they work is thought to enhance the activity of GABA by inhibiting okay it's probably one of the only ones that does this inhibiting the neuronal uptake um so GABA is a neurotransmitter so it gets usually pulled back up into the nerves um to be reutilized and recycled and by blocking the re-uptake of that it sticks around longer so it can work on the GABA receptor this is kind of like uh triccyc that inhibit the re-uptake of norepinephrine and serotonin and same thing right um so that's it that's what makes it different it is a major substrate of 3A4 and as a result it is subject to clinically relevant uh drug drug interactions and because GABAent I'm sorry GABA which is an inhibitory neurotransmitter sticks around for longer obviously it makes sense why they have drowsiness weakness being a common complaint now topamate is used and is uh showing up more in practice And it's primarily used outside of uh its seizure treatment for migraine prophylaxis not acute abortive treatments but migraine prophylaxis Uh on occasion it's also used for essential tremors Uh you might see that as well How does it work well it's multiffactorial Blocks those sodium channels So it uh makes the um cell more likely or less likely to be depolarized It enhances GABA which is that major inhibitory neurotransmitter and then it antagonized the glutamate uh receptors Now what's not listed um up here is that it inhibits carbonic and hydrates activity and that's not and that's because it that doesn't really benefit us so much in seizures but it is a problem as it relates to side effects and I'll mention that here in a minute Now when you look at dosing when the clearance drops below 70 now you saw with gabapentin less than 60 and pregablin but with topyramate less than 70 and we don't usually t to start dosing drugs renally until we get below 60 but there are a few drugs and this is one of them that you have a weird kind of cut off you know where we start to do that All right Um so when you look at side effects um same sort of things weakness you know changes in in vision but the one change in vision that you want to uh be aware of is an acute angle closure glaucoma This is considered a medical emergency And this is where basically the uh the humor the fluid in the anterior chamber of the eye cannot drain off And as a result of the accumulation in the anterior chamber it pushes back onto the optic nerve and that can just like with glaucoma cause blindness but it does it very quickly and rapidly and so uh you need to stop this drug and never obviously use it again Metabolic al acidosis can occur because of the reductions in by carb from the carbonic and hydrates activity it has been associated with nephrolithasis and smaller amount of hyperammia Okay So really key side effects here um being big ones that you should memorize for sure that's unique and then then the indication with migraine uh prophylaxis Okay Locosomide or Vimat it's an adjunct uh in patients who are and for age greater than age 17 it is available um orally and IV and the dose is the same for both no one really knows the main mechanism uh but uh it may selectively block uh this slow inactivation so what that means is it will once that nerve depolarizes remember there's a period of inactivity it it slows the recovery phase of that it also binds to this thing called collapsin response mediator protein 2 which is pretty unique um in compar to the other anticonvulsants because this is affecting differentiation and axonal growth the impact on that from a pharmacologic sort of biologic effect and as relates to seizures is not really fully known at this time Now unfortunately it is also just like with phenotin associated with dress Um again remember that's the drug reaction with eocinophilia That's where the E is drug reaction And then they have systemic symptoms which usually includes uh a rash and other sort of organs being affected Um and it also can cause a kind of like a first excuse me firstdegree heart block PR PR interval prolongation So on occasion um these patients especially with underlying structural heart disease may need to monitor EKGs Uh lavator acetam or kera uh is gained a significant amount of use in practice and is now used for a number of different types of seizures Myoconlonic tonicclonic seizures It's actually gone headtohead uh with carbomasopene and shown to be equivalent And so there's actually some decent data uh supporting its use Uh status epilepticus is it's being used more and more for but that's an off label And then I would also mention here uh that it's being used in traumatic brain injury prophylaxis against seizures So in TBI prophylaxis uh we use it uh after traumatic brain injury for about 7 days to prevent seizures during that period Then we just stop the drug But this is one of the medicines in addition to phenotin and phosphenitoine that's being used in clinical practice So you might see that more being used in the future and people like this drug uh because you don't need to necessarily monitor it although you can order levels depending on your institution Um and you uh there's no major drug interactions and it it seems to work The only downside to it is that it needs to be really dose adjusted and we'll come back to that here in a minute the dosing No one knows the exact mechanism You see that I got four bullets listed here Uh the one that I think is starting to gain probably more attention um is this one down here the synaptic vesicle proteins to a lians um because this is affecting neurotransmitter uh release Uh but you can see that it works on calcium um it facilitates GABA related activity and also the potassium current which is um going to affect again the charges inside and versus outside the cell We start out at a low dose like somewhere around 500 milligrams once to twice a day and then you increase every two weeks to a max dose of 3,000 milligrams The exception to the rule is if you have impaired renal function and look at this one less than 80 Okay Then you start to reduce the dose and the max becomes 1,500 milligrams You don't even really have to have much renal impairment before you have to be careful with the amount of drug that you start to use Now the good thing about it from a dosing standpoint and clinicians love kind of like Vimpad is that when you have an IV and an oral drug that has the same dose that's great because the bioavailability when administered by mouth is approaching 100% which is what it is when you give it IV Uh it's a 15minute infusion So it's very convenient for nursing staff to administer It's very convenient in a number of uh settings both inpatient outpatient It's overall fairly well tolerated Uh you see here the only downside is this is behavioral problems Um this shows up in in mainly in patients with pre-existing neuroscsychiatric conditions that are either not diagnosed or have been diagnosed and are difficult to control Uh outside of that um it really is a little bit of just some weakness Um for the most part pretty well tolerated As I mentioned no major drug interactions through phase one cytochrome P450 system We just have to really dose adjust it And again weird dosing is starting at less than 80 which is not normal We usually start less than 60 And then as I mentioned there's actual data Its use going head-to-head with carames use in traumatic brain injury And so we're starting to see more and more of it being used because we don't also have to monitor it Although I said depending on your hospital or institution there are assays that will measure the level for mainly to determine appropriate compliance and adherence more than anything All right So there's a analog of levocacetam that has come out Uh again really no significant benefit to my knowledge or experience but it works on that specific synaptic vessel uh protein liand 2a that affects neurotransmitter release Um really no significant advantage there uh vigabatrin Um this is used um kind of like a there's a it's a weird um condition uh where patients have these infantile spasms um and it's as a result of some bad side effects It is under a restriction of access um which probably is why you don't see it used very much But the way that it works is remember GABA being the major inhibitory neurotransmitter does also get metabolized It gets uptake by the nerve but it can also get metabolized and it's one of these irreversible inhibitors of the enzyme GABA transaminase and so basically allows GABA to be around uh a lot longer Now the side effect that we're most worried about and the reason that it has a restricted access is due to this irreversible peripheral visual field defects that because of effects on the retina Um and so they need baseline uh vision testing and then um every 3 months while they're on treatment have to go repeated testing um to make sure that that obviously isn't happening Okay On occasion uh these patients can develop um some edema may need MRIs What that does you know what it translate to I don't know but it's just some abnormalities that have been identified So again it's really restricted to a specific patient population Um and it's very expensive Okay Okay All right Zonissomide or zonogram uh it's been around for a while actually uh but it's not really used for much of anything else like topyramates used for migraines and ltodals mood stabilizers and all that stuff Zonissomide really is just reserved for seizures Um it it works possibly blocking both sodium and calcium channels So this is going to decrease the depolarization process and this is going to reduce neurotransmitters um and regulation of neurotransmitter vesicle movement in the nerve Um nothing really big The big one here is that kidney stones um which we saw also show up a little bit in topamate So we really need to counsel and encourage hydration There um are concerns or cases of hyperothermia especially in children This may have something to do with maybe sweating or inability to regulate their uh thermmorreulatory centers of the brain and so they're at higher risk of developing hyperothermic um type of situation The other problem that I think probably outside of those two side effects that shows up on boards is the sophonomide moa This is obviously not a nonimicrobial sophonomide And it's important to recognize that sophonomides are not all the same the the groups and how they're arranged are different between microbial such as sulfomthoxazol and trimethoprim or bactrum uh versus non antibiotic non antimicrobial agents but regardless because of the risk and because Stephven Johnson syndrome if it should happen is a life-threatening skin reaction we just tend to avoid it in patients with a sulotibo uh sulfur allergy Um but that's really the issues with it Um so prampanol uh this is again reserved for partial and as an adjunct to general tonic clonic seizures Um it's working on that ampa receptor which is what glutamate is binding to Uh so glutamate again being your major excitatory neurotransmitter It's kind of blocking those All right Um yeah blackbox warning This is the big one with that right right here So dose related serious and life-threatening psychiatric um events They become very aggressive hostile they can have some auditory hallucin hallucinations um and in the first six weeks So if they have underlying uncontrolled psychiatric illness kind of like what we saw exacerbated a little bit with levitator you got to be careful with its uh use which is why it gets a blackbox warning And anytime a drug has a blackbox warning those are the kind of things that you know boards and stuff like that want to make sure that you know Refinomide is used for Lenogus thought syndrome Remember that's a kind of a combination of abs seizures mildclonic seizures and stuff and they they have these abnormal atypical absance pro um symptoms associated with their disease So it's there aren't many drugs that are used for this condition but this is a newer agent Um and it prolongs the inactive period So remember as the depolarization occurs and sodium moves inside of the cell then there's that inactive state and this basically prolongs that inactive state to prevent the nerve being ready to receive another basically nerve impulse Um it is a weak inhibitor of 2E1 uh there's no IV dosage formulation but it is associated with shortening of the QT interval and so if a patient has underlying cardiac condition of QT um shortening syndrome then they uh they would be contraindicated in those patients I've quantity never seen that uh before clinically but that doesn't mean it doesn't exist I just it's very rare so what I try to do with some of these is summarize some of the mechanisms you know to put things into to to like what target So if they ask you if they're trying to wrap your mind around it I don't know if this kind of stuff helps you uh or not But um what it's intended to do is to lump them into groups so that you can sort of memorize them that way Obviously the drugs that inhibit sodium channel especially our older agents like phenotin carbomasopene um oxarbazopene those kind of drugs those are going to be more common u things that we see the ones that affect GABA predominantly uh you know are going to be unique Levitaracetam has a very unique specific mechanism So you know the the point here is to try to just make it a little easier for you I recognize it's complicated and frustrating but the reality is depending on what you read you get a little bit of a different response which is you know in itself frustrating So take-home points core concepts from these le this lecture is that you want to select the right drugs for the right indications Hopefully you've seen that we have a number of drugs with unique indications and very narrow focuses Sometimes you want to individualize that therapy educate both the patient if they can be educated based on their mental status Uh but more importantly sometimes it's the family for monitoring especially some of these drugs that have side effects that are more concerning Uh monotherapy is again majority up to 80 patient 80% of patients will respond Uh but on occasion we that's why we have so many adjunct um options Uh so just keep that in and keep that in mind And then monitoring obviously drug levels especially in those older agents like phenotin carbomasopine valproic acid phen pheninoarbatital being more common Um and then don't forget about drug interactions This is a big one especially with those enzyme inducers being uh problematic um like phenotin carbomasopene pheninoarbital primadone you know those are sort of our more problematic drugs that can lower the concentrations of other medicines and cause therapeutic failures And then lastly don't forget some of those drugs that have some weird renal dosing you know like levitraetam and um stuff you know because it's just it's outside of our normal thought process and normal criteria for where we start to make renal dose adjustments So hopefully you found it to be useful