Speaker 1 00:00 Alex, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University, College of Pharmacy. We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. And now Unknown Speaker 00:29 on to the show. Dr. Sean Kane 00:31 Welcome to Episode 27 of HelixTalk. I'm your co host, Dr. King. I'm Dr. Schuman, and I'm Dr. Patel, and we're resuming our previous episode, Episode 26 where we're reviewing our top drugs or drug classes in the past 20 years. To recap, my drug of choice was sildenafil Speaker 2 00:48 or Viagra. Mine was fomax or tamsulosin, Speaker 3 00:52 and mine was the new TNF inhibitors, particularly HUMIRA or Adele mummam. Dr. Sean Kane 00:58 And today, what we're doing is we're completing this off with our runner up, if you will. So numbers four, five and six of our most pivotal drug classes in the past 20 years. Dr. Schuman, you want to kick us off? Yeah, I'll kick it off. Speaker 2 01:10 And I'm going to start right off the bat is I cheated a slight bit, and that one of mine was approved initially in 1993 since it came out at an extended release in 19, I believe, 97 and then the other agents have come out within the class all the way to 2013 I think it gets a pass, if you just allow me that little bit of flexibility. Mine's going to be the SNRIs, or the serotonin norepinephrine reuptake inhibitors, a class near and dear to my heart in the mostly in the psychiatric world, but you can see them used in other places. Speaker 3 01:41 They sound very much like the SSRIs. So what is the difference here? Alright. Speaker 2 01:46 So the difference is we would go, we went back historically all the way to the tricyclics, antidepressants of the monoamine the monoamine oxidase inhibitors, and we have these very large, almost shotgun approaches to hitting our neurotransmitter serotonin, dopamine and norepinephrine. And we also noticed a whole lot of drug, drug interactions with the maize, and then a whole lot of issues with cardiac issues, nausea, vomiting, risk of so overdose, intentional, accidental, with tricyclic. So they backed it off and narrowed the focus down. Came up with the SSRIs narrowed down to three neurotransmitters to one, and then we expanded that scope a little bit with our SNRIs. And so they work on both serotonin and norepinephrine. So you get the benefit of some of the arousal mechanisms of norepinephrine, as well as some influence on anxiety. Dr. Sean Kane 02:37 So if you had to, you know, explain to a patient, let's say you know two sentences or less, in terms of what you gain from the SNRI quality, or the norepinephrine reactive quality versus an SSRI. What? What could you get pharmacologically out of that? Speaker 2 02:54 A lot of it is going to come to patients will often say that on an SSRI, their depression is not as much there, but they don't really feel anything kind of feel flat. And so the addition of the norepinephrine allows some things to bubble up a little bit, so you get a little bit more of an ability to have some ups and downs, and a little bit more of the ups in moods, and as well as a little bit of maybe some benefit on anxiety. And then there even may be, as we alluded to with the last of the agents is a little bit of an improvement, potentially in cognitive, cognition or mental processing. Dr. Sean Kane 03:26 And I don't want to mislead the audience too much. You're not saying that s enter is or superior in depression therapy to SSRIs, right? Speaker 2 03:33 No, no, no, not necessarily the fact that they're, you know, as efficacious based upon the the star d trial, but it just gives us an extra option should there be, you know, based upon comorbidities that may present themselves. Dr. Sean Kane 03:45 Okay. So what was the first player to the SNR, AG, crowds, Speaker 2 03:49 the first player, again, was venlafaxine, or Effexor, came out in an immediate release form in 1993 good medication. Nice thing about it, though, is it was usually taken up to three times a day for that full effect. And again, it was approved for major depressive disorder initially. And what's neat about it, and allows for this flexibility within the class, is that at low, low doses, it's an SSRI, and then as you get it has a well concentration dependent, it starts to engage the source of re uptake on norepinephrine when you hit about a dose of most people would say 150, some would say 225, but around that range, it starts to have the additional effect. So we usually start with that medication around 37.5 milligrams, 75 milligrams, and titrate it up over time and to be able to get that, that dual reuptake effect. And then what they noticed, though, is, you know, you could do some some higher doses, but usually there was a fair amount of side effects, all the way up to, you know, to 325, 75 milligrams. So what they did then in 1997 is, they come came up with a second or an extended release form of it affects our XR, and that's the one that's that can be given. Know, once a day, generally, more well tolerated, more easy to remember. And then that one, they've gone ahead. And it's also got approvals for Social Anxiety Disorder, generalized anxiety disorder, as well as panic disorder. Speaker 3 05:13 And I think I've seen this used in maybe off label in patients who have menopausal symptoms and hot flashes. Speaker 2 05:19 Yep, you'll see that. You'll see that as well, potentially, again, off, off way before that. And so that was our initial agent. And the one thing about that one is, again, it's still fairly serotonergic, so you still run into the issues with nausea and vomiting you sometimes see with SSRIs. And some would argue too, that since you have to titrate it up to an effective dose, some individuals kind of quit before it gets to that full piece and cite failure. Dr. Sean Kane 05:47 And then, with this addition of the norepinephrine quality you talked about higher doses, more side effects. Does that norepinephrine reuptake inhibition provide any kind of detrimental adverse effects? Speaker 2 05:58 Sometimes, again, because norepinephrine is involved in arousal mechanisms, which is can be both good and a bad thing, too, much of it, hyper arousal, jitteriness, sometimes changes in blood pressure or tachycardia can sometimes occur at the higher doses of it, and that's something you will occasionally see. And so then the next one in this class came out was one a lot of individuals are familiar with duloxetine or Cymbalta. This one was approved in August of 2004 and this one has many indications; they've really gone for a whole ton with it. It's approved for neuropathic pain, generalized anxiety, fibromyalgia, chronic musculoskeletal pain. And then it's even approved in Europe for stress, stress related urinary incontinence. And it can this another place where it's used off label in the United States, does been, ended up not going through the approval here, at least not yet. And then they most recently actually approved it for generalized anxiety and pediatrics, anyone over seven and older. That was approved in August of 2014 actually. And this one's unique in that generally, right out of the box, if you will, can have a pretty good effect on both serotonin and norepinephrine. And that's what distinguishes this. When you don't titrate it up and then get the norepinephrine effect right out of a box at your you know, 30 milligram doses or so it has both of those pretty much in a close to a one to one balance. Dr. Sean Kane 07:25 I think this one's interesting, because even we're not even talking off label indications, this is an FDA approved indication. Are almost non psychiatric indications, like chronic musculoskeletal pain, fibromyalgia, I think you could argue a little bit of a psych component to it, but definitely with chronic musculoskeletal pain, it could be very awkward as a pharmacist to be counseling a patient about their depression when they're actually filling it for chronic pain. Speaker 3 07:51 Yeah, that's true, and I think nowadays, with the improved pain management strategies, the providers always try to look for a source of neuropathic pain. And I've used, I've seen Cymbalta as being one of those main medication used to control the neuropathic side of the pain, Dr. Sean Kane 08:08 and for the critical care providers out there, Cymbalta is not my favorite SNRI in the ICU setting. The reason is that it's not crushable, so it can't be put down in ng or no G tube, and there's really no good alternative, unless you start playing around with giving them IR vin lifaxine or something like that, that I'm really not keen to do. So for that reason, I wish that there was some immediate release version of it, but there's not. But that also makes it a very attractive option on the outpatient side, given that it doesn't have to be taken tid and have kind of issues with, you know, frequent dosing Speaker 2 08:41 right now with this agent is one thing we do sometimes note, is dry mouth. As we increase the norepinephrine, dry mouth sometimes becomes of concern, as well, as we mentioned about urinary incontinence. So it can be beneficial at that. But then we also run into the issue about urinary retention becomes an issue with this one. And then we'll, we'll we'll start kind of moving on. These two are by far the ones that are most likely seen in practice. We'll briefly touch on desvenlafaxine, or Pristiq, which is one of the chief 'me-too' medications. That's the active salt form of O-desmethylvenlafaxine. And so that's the breakdown product of venlafaxine. A little bit more of that norepinephrine than venlafaxine. Otherwise fairly similar, starting dose of 50 milligrams a day. And really, the FDA, based on side effects, doesn't really encourage going up too much higher on it, so you're somewhat limited. Really, maybe 100 milligram dose. But really, that one you kind of stuck at, you know, giving it a 50 and seeing what happens. Dr. Sean Kane 09:39 And when you say, Me too, you're referring to the idea that sometimes drug companies get new approvals that kind of extend their patent to be able to kind of make more money on an existing product by repurposing it or repackaging it in a slightly different Speaker 2 09:53 variation, certainly, or in this case, even just, you know, cups taking the medication and picking, you know, an active metabolite. And then making that the new drug, and so that, you know, again, it has a little bit of a different profile. But unless you have a patient who's a known poor metabolizer of the enzyme system, sipd Six, there's really not a whole lot of reasons to choose this one over one of the Speaker 3 10:15 other agents. And you probably want to go back to our older podcast where we have clearly expressed our dislikes about the strategy of, you know, taking out the most active enantiomers and using that as a marketing strategy. Speaker 2 10:29 Yes, Dr. Patel, we could go into that a lot, but yes, certainly we have discussed that in the past, and then within them we are then we also have, briefly as legal of mil NASA, prana Savella, which is the next one, a little bit more of this norepinephrine reuptake compared to serotonin. And this one's actually only approved for fibromyalgia, and that was in 2009 and then they actually it's approved in Europe for depression. So then what they did here is they came out with another of these, almost me too, like so Levo, mil, NASA, Pran, one of the two enantiomers, or that this is one that's available in mirror image forms of the drug. And so they picked the more active one of those, the Levo form, called it festima, and in July 2013 approved that one for major depressive disorder. Now this one's interesting, because this one has the most norepinephrine of any of these, so which means both a little bit more of a risk of urinary intention, as well as, again, a little bit more of that, that arousal, so much that they acknowledge that you know it potentially, you know right now, there's no indication for it, but it potentially could be beneficial for individuals, again, who, as part of the Depression, have some Psychomotor retardation, or, again, or some of Those issues with cognitive process. Speaker 3 11:41 So I've had a lot of patients, and again, this medication kind of creeped up on me, per se, if we were to say so, because I didn't see whole lot of advertisement for it. But all of a sudden I saw patients in the clinic being switched from Cymbalta for their fibromyalgia to Sabella, because it was a new medication out there. So can you kind of allude to the facts as to how this is different in terms of treating fibromyalgia when it's compared to Cymbalta. Speaker 2 12:05 Oh, yeah. So monasapran, or the, you know, the racemic form of it is, again, just a little bit more of that norepinephrine. And so, you know, if you look at that being one of the primary mechanisms that we believe with fibromyalgia inhibiting some pain, you could say, Okay, a little bit more of that could be more advantageous. However, I would be cautious about extrapolate too much that I about it being, you know, infinitely more superior than that one. It's certainly, you know, you may get a little bit of a difference in the mechanism, but whether that correlates to, you know, to outcomes, I'd have to see so Dr. Sean Kane 12:41 and Dr. Schuman, you know, of these latter agents where they have more of this norepinephrine? We talked a lot about pain, fibromyalgia and depression. Do they have as much of a role in, let's say, anxiety, where that norepinephrine may not be an advantageous Speaker 2 12:55 component, that's always been the issue. When we treat our population with PTSD, we often run into a sort of a jitteriness that can come about from these agents, and that we've witnessed, and it seems, you know, it's documented in the literature, but we've, we've noticed in our population, to where we sometimes will will back down to an SSRI, or if we're using venlafaxine, we'll go back down to 150 or below to bring it back down to more search synergic mechanism, because we do notice some of that, more arousal, and that, of course, becomes the issue with with PTSD. But these medications, you know, the class as a whole, is considered to be level A evidence for treatment of PTSD. But you just gotta, gotta watch for for that in certain patients who are very sensitive to that norepinephrine Dr. Sean Kane 13:42 Well, Dr. Sherman, I think I agree with you that the SNRI drug class is a logical adjunct, not better, but a good adjunct, to the SSRI class, and that we get that norepinephrine component that could be helpful in certain patients, but definitely not a replacement for the SSRI drug class. Speaker 3 13:58 And I think one thing we also need to make clear to the audience is to that, you know, probably adding an SNRI to an SSRI, existing therapy is probably not a good idea because of possible drug drug interaction and serotonin syndrome risks, right? Speaker 2 14:13 If we, if we want to, you know, keep a lot of that serotonin activity you can always keep with a venlafaxine. You don't need to just add an SSRI plus a duoxetine or an SSRI plus levomanosophy, and we that's what I think, is. The beauty of this class is we have versatility, so that we can look at an individual patient and look at what they're approved for, as well as look at the ratios of those two Dr. Sean Kane 14:37 binding affinities. So kind of move into the next seminal or pivotal drug class. Dr. Patel, what? What is your number two go to agent here. Speaker 3 14:46 The number two agent that I was interested in talking about is Plavix. We know that now it's available as a generic called clopidogrel, and it's a P2Y12 inhibitor on the platelets. So originally, it was approved back in 2002 and then we had a generic one that come out in the market. But then it was pulled back shortly after being introduced in the market because of some patent infringement. And then finally it reappeared in the market in 2012 with proper patents, and, you know, not missing any regulations and whatnot. So one or actually two different doses are available in the market, the 75 milligrams, as well as the 300 milligrams. And currently we are using it for various different indications, such as unstable angina and semi semi patients who have had stent placement, patients who have had percutaneous coronary interventions, any recent mi stroke or even peripheral artery disease. And it has some off label using in patients who have afib, especially patients who cannot be on Warfarin for any given reason. Dr. Sean Kane 15:58 So I think for me, at least one of the reasons that this is such a pivotal drug, and frankly, drug class, is that it's so versatile in that. I mean, think about how many indications you just mentioned it for. These are FDA approved indications, except for the afib. You know, it's extensively used in a number of different disease states. Patients frequently call it a blood thinner, but from the pharmacist in me wants to just call it an anti platelet agent, but for patient counseling purposes, most patients will refer to this as a thing that thins their blood, like aspirin does Speaker 3 16:27 absolutely and thanks for mentioning aspirin, because aspirin has got these wide range of indications as well. And you know, Plavix was clearly approved by FDA based on one trial, and that was the CAPRIE trial that was conducted in the 1990s. A few years after the approval of Plavix, we had similar agents in this class category, Brilinta and Effient were also approved in 2011 and 2012, respectively. Speaker 2 16:56 Dr. Patel, my understanding is that this medication is a pro drug. Could you comment upon how any of the implications of that in terms of its use? Speaker 3 17:04 Yeah, absolutely. So it is a pro drug, and it needs to be activated for it to work. And so basically there is an activation and there is an actin metabolite that is a thiol form. This actin metabolite then goes to the P, 2y, 12 component of the ADP receptors on the platelet surface, and then irreversibly blocks it. And so the end result is inhibiting the formation of the GP two, b3, a receptor complex. And then this results in inhibition of platelet aggregation. And it once it's taken, one dose is taken, it kind of lingers. The effect is stayed in the body, in the blood, for about seven days. So you know, for for your patients who are taking Plavix regularly and undergoing a procedure, if you want to make sure that they're stopping it seven days Dr. Sean Kane 17:50 before, in terms of adverse effects, because it is a quote, unquote blood thinner, but really an anti platelet agent, I would assume that we can kind of come up with some of the adverse effects that you would anticipate from an agent like that, probably hemorrhage, bleeding, bruising, things like that. Speaker 3 18:05 Yeah, absolutely. So you want to warn your patients about common bleeding and bruising side effects, and you know how to identify some of those, such as, you know some spotting underneath the skin that will be your purple, blue spots that could be bleeding, micro vessels, bleeding that would be your bruising. Besides the bleeding and bruising, some trials, I will also noted skin rash as being one of the common side effects as well. And then we're going to talk about how, when it entered the market, it was a game changer. And now, with the other agents being on board, and some of the newer findings on how inter patient variability, especially with genetic polymorphism, how it affects the metabolism of this medication, and thus the effect of the medication too. So as you alluded to, the fact, Dr. Kane, you know why this was a game changer when it came out in the market, because it had multiple indication, okay? And as I mentioned already, too the Capri trial give out all the indications possible. And at that time, it had shown to be the drug of choice for the secondary prevention of stroke. But then we also have another agent called Aggrenox, which is the combination of aspirin and dipyridamole, which kind of showed similar outcomes compared to Plavix as well. So here we're just playing with basically the cost of the medication. You know, clopidogrel has gotten generic. So has the brand, Plavix. So whatever that's covered on patient insurance, we can go ahead and use those instead. One thing I do want to mention is that it is a good option in patients who have aspirin allergy, or if they cannot use aspirin because they have asthma or related issues, we can go ahead and use Aggrenox instead. Dr. Sean Kane 19:45 and thinking about the agronox versus Plavix issue, another common complaint of agrinox is pretty profound headache. About one in three patients will have clinically significant headache on that medication. It gets better with time, but oftentimes that's intolerable to. A patient, Plavix just does not have that adverse effect associated with it. So another reason why you might go Plavix over agronox, depending on the indication and things like Speaker 3 20:09 that, absolutely correct. Now, Dr. Kane, I know you were very versed when it comes to the genetic polymorphism and how this medications response differs from patient to patient. I would probably like to use your expertise here, and, you know, maybe say a few things about, yeah, what you think about that? Dr. Sean Kane 20:26 So, like we said, Plavix itself is a pro drug, so it has to be activated by the liver into its active form to be able to inhibit platelets to cause you to not have a stroke or not have a heart attack, or, you know, things like that. It turns out, though, that the enzyme that's used to activate Plavix has a lot of polymorphisms depending on primarily race, so Asian descent as an example, tend to have a polymorphism that makes it so that they don't metabolize the drug as well into its active form. So less active form means that you're at risk for things like heart attacks and strokes because you have less active drug that gets created in the body. Speaker 2 21:03 And that's something I think we have to distinguish between it being a pro drug and other medications, because sometimes we think, okay, if a drug can get metabolized, then we think maybe that you're going to get, you know, an increased level of the drug. But in this case, it's more of the opposite, because we can't activate it, therefore it's effectively useless, exactly. Dr. Sean Kane 21:21 So that's one thing that has come out of the literature, is that a good number of patients are going to have polymorphisms that primarily will decrease the effectiveness of Plavix. But there's even certain polymorphisms that increase this conversion to the active product, will increase the risk of hemorrhage, bleeding, adverse effects like that. The other interesting thing is that it seems like certain drugs are able to block this pathway of the conversion, and kind of the main drug of interest is omeprazole, or Prilosec. Oh, the purple drug, the purple one. And this is interesting because we had good lab data showing that in a test tube, at least, that omeprazole blocks or inhibits the enzyme CIP, 2c, 19, that's responsible for this conversion process. So there's a study done in a VA population where they looked at everyone who got Plavix, and they split them off into people who got Plavix with a ppi, omeprazole, primarily because of formulary reasons, versus people who got Plavix, who were not on a ppi. The problem, though, is that the people who received the PPI were sicker at baseline, so they had more comorbidities, they had more hospitalizations. They were just sicker. But mathematically, we're able to kind of correct for the fact that we have the sicker patient population. And what they demonstrated in the trial was that people who got a PPI omeprazole on top of Plavix were at a higher risk of thrombotic events like heart attacks and strokes. The problem with the trial is that because of its retrospective nature and the mathematical modeling that was required to make the two groups similar, there was a question whether the drug interaction was a relevant drug interaction, or if it was just kind of a chance finding that was found in the statistics, not in clinical practice. Speaker 3 23:04 And so I think following that study and a few other evidence that has been out there, FDA has put out the statement that if you must use pavix as a drug choice, and if the patient must needs to use a ppi, then a drug of choice for PPI should be pentoprazole. Is that what you usually do in common clinical practice? Dr. Sean Kane 23:24 Yep, so pantoprazole in a test tube doesn't seem to have this effect. And of the data that we do have of actual patients, it seems like pantoprazole does not increase the thrombotic risk. I'm a little skeptical whether the omeprazole interaction truly exists or not, but I also wouldn't want to chance my luck, in the sense of, if you can pick pentoprazole, why would you not do that, given that we have some data that there may be an effect with omeprazole. Speaker 3 23:49 Thank you for that input. So turning the table to you, Dr. Kane, what is your second favorite medication, or class of medication that you're going to talk about today? Dr. Sean Kane 23:59 So my second pivotal drug is going to be Keppra. The generic name is levetiracetam, and this was approved in December of 1999 and one of the reasons that I like this so much is from a branding perspective, the drug manufacturer was genius in creating the generic name. No one can pronounce the generic name, so everyone uses the brand name, even though it's now a generic product, everyone still calls it kepra Because it's so difficult to pronounce. Levetiracetam scores one point for the drug manufacturer in that standpoint. But if we kind of look historically, before the drug was approved in 1999 all of our other anti epileptics were really horrible options. So nearly all of them have kind of negative neuro sensory adverse effects, everything from sedation to feeling mental cloudiness to in coordination, we just look at a couple of the big players. Phenytoin has rash and increases your LFTs, carbamazepine and oxycarbazapine decrease your sodium levels and potentially your white blood cells. Valproate. Acid has a host of black box warnings, everything from liver damage to hyper anemia to weight gain to alopecia. Lamotrigine, you can have a very severe, life threatening rash with that. Topiramate can kind of blur your cognition. Gabapentin, pregabalin cause a lot of sedation peripheral edema. Phenobarbital is FDA approved as a sedative. Obviously, it causes a lot of sedation. And really, you know, many of the drugs that I just mentioned, we actually draw drug levels on them because the therapeutic window is so narrow, meaning that we're not comfortable having the patient have high levels, because we see a lot more toxicity as the Speaker 2 25:36 level goes up. So can you draw a level of the Levitra acetam? Dr. Sean Kane 25:41 You can draw a kepra level. The problem is, what do you do with it? So one thing is the therapeutic window of kepra, as opposed to or many of our other antiepileptics. The therapeutic window for Keppra is very, very big, meaning that we're comfortable giving much bigger doses and not worrying about drug levels. Generally, it has more predictable pharmacokinetics than some of our other agents, it doesn't go through the liver, like many of our other agents for epilepsy do. Instead, it relies on the kidney to leave the body, which kind of brings up a lot of other issues in terms of renal function, as opposed to drug interactions from the hepatic point of view. And then finally, we don't really know what, no one agrees, at least on what is at therapeutic kepra level. So you can get a level and say whether they have Keppra in their body, but there's no Well, agreed upon range of a Keppra level. Speaker 3 26:27 Well, I guess that's a good thing that you know providers don't have to worry about over toxicities, because it has the such a generous profile when it comes to toxicity levels and whatnot. So you mentioned some of the side effects. What are those side effects about kebra? Dr. Sean Kane 26:42 So in general, especially in pediatrics, you can see some agitation, but it's, from what I've read, at least, not a game changer in terms of the agitation that you'll see for adults, what you can see is some of those behavioral changes, like anger, depression, irritability, probably less common in adults. In the packaging, you will see some sedation, but it's definitely less sedating than almost every other anti epileptic on the market. And you'll also see fatigue or lack of energy, but again, still way less than most of the other anti epileptics in the market. So if you kind of compare it in terms of adverse effect profile, it's really night and day between Keppra and all of the other agents on the market. Speaker 2 27:20 It's interesting because we occasionally will be fearful of it at our at our practice site, due to the potential for some of those, you know, increase in agitation or irritability. But then when you look at those drug drug interactions, you know, if we're putting somebody on valproic acid, now we're looking at the LFTs, and then we're looking at the hyper anemia, or we're considering carbamazepine, and now we're, you know, we're monitoring the sodiums Day and night to make sure they don't drop. You have to really think, okay, you know, if there's that small risk of behavioral changes, you know, where does that fit in the spectrum compared to what we fairly know is a lot more likely some of these other agents, yeah. Dr. Sean Kane 27:58 So I wouldn't say that it has no adverse effects, but I would definitely say the adverse effect profile is way more tolerable than any of the other agents on the market. From the ICU perspective, there's a couple things that I really like about kepra. One is drug interactions are fairly minimal because of its renal elimination. Two is it's a one to one, IV to PO, so we have an IV version of it, and it directly converts milligram between oral and IV and three, you're not supposed to crush the tablets, but they do have an oral suspension that is just as cheap as the tablets are. So for our intubated patients, we can use a liquid and it's very easy to administer that you don't have to worry about not crushing the tablets to give it orally to a patient. Speaker 3 28:38 So let me count some of the good things about kebra, you mentioned a favorable therapeutic range, favorable kinetic profile, meaning it goes to the kidney, not to the liver, so less hepatic related metabolism, drug interaction. It has favorable ADR profile. It is generic, it's available in versatile dosage forms, and it's cheaper. So it sounds too good to be true. What's wrong with Keppra then? Dr. Sean Kane 29:02 So there are a couple issues with Keppra, and some are bigger issues than others. One thing is that we really don't have a good understanding of how it works. What I mean by that is many of our other anti epileptic slow sodium channels as an example to make it so that it's harder for your neurons to fire to be able to propagate a seizure. Others work on GABA, again, same principle making it harder for your nerve or your neuron to fire with Capra. If you look in the packaging for it, it says that it's a synaptic vesicle glycoprotein, SV two a inhibitor. What that means, or what it does, or even what the SV two, a binding site, does in epilepsy, we really don't have a good understanding of that. It's not necessarily a downside for the drug, but it means that clinically, we have less appreciation for how it works and anticipating some of the adverse effects and things like that. It's kind of a black box in terms of you give it, and they tend to have less seizures. Some of the other downsides are that actually has fairly limited FDA approved. Approval for its use. So in the US, it's FDA approved as an adjunct, meaning that it's your second agent that you add on to a patient who has epilepsy to you add it onto their regimen. And because of that, officially, if you're going by what the FDA approval is, you're only adding it to a patient, as opposed to having it as monotherapy. With that said, though it's extensively used for monotherapy, and there is data to support monotherapy use, this is not an FDA approved indication, which means that it hasn't kind of undergone this rigorous process of approving it for mono therapy, Unknown Speaker 30:33 but providers do it anyways all the time. Speaker 2 30:35 Yeah, they say we have, you know, it's nice, because again, of the drug drug interactions, we have less of the white blood cell count concern with our Clozapine patients, and so it's been nice if you have an individual who's either they're concerned about seizures, who has already had seizures on the Clozapine, then we usually they'll go and add the Levitra acetam as the option, because we know it's not going to knock down the WBCs like you may see with the Depakote, and it's not going To have all the host of drug drug interactions with some of the others. Dr. Sean Kane 31:04 And if you're a provider, if you think about it, you should have a lot of weariness to add on phenytoin or carbamazepine or valproic acid to a patient, as if you're not, kind of a neurologist, because of the adverse effects that you see because of the drug drug interactions. Whereas with kepra, it's kind of an agent that's very easy to use, very easy to dose. There's no drug levels. Generally you don't get in trouble with adverse effects. So for kind of the layman, if you will, prescriber, it is way easier to just add on kind of knee jerk, as opposed to some of these more serious anti epileptics that we have available. Speaker 3 31:41 And if you ask me, probably, and if I was a clinician prescribing any kind of anti epileptic medication, probably Capra will be my go to drug. Speaker 2 31:48 And the only thing that could make me sour on this one is if, for some reason, they did a patent extender, or had it in some sort of a me too version. Dr. Sean Kane 31:54 It's funny, you mentioned that. So in 2008 the drug company came up with an XR version of Capra. So Capra XR and this has the advantage of being once daily, as opposed to twice a day, which Capra is almost always twice a day, unless you have very bad renal function. So does that Speaker 2 32:11 sour your I'll give them the benefit of the doubt, since we can just do it once a day. That's That's nice any although, you know, anytime you have different names, it can be a little bit confusing. Dr. Sean Kane 32:21 Yeah, so Metoprolol, in my mind, is the best example of confusion, and that is more confusing because of the differences in salt forms, succinate versus tartrate. But in terms of, if someone's used to Capra XR, they're probably more likely to have a medication error in dosing normal Capra IR once a day as opposed to twice a day. And the vice versa is true as well, and giving a patient XR B ID, when it really is only intended to be given daily, again, for people who aren't neurologists, who are less familiar with anti epileptics who are prescribing kepra, there is that risk that they don't appreciate the differences between the two, and they assume kepra XR is what people use where really it's fairly uncommon to use Capra XR. All right, so to review, Dr. Schuman, what were your two pivotal drug classes in the past 20 years? Speaker 2 33:11 My two pivotal drug classes were going to be the alpha one, a antagonist, so tamsulosin and other medications for treatment of benign prostatic hyperplasia. And then my second class was the serotonin and norepinephrine reuptake inhibitors used primarily for treatment of major depressive disorder, those certain agents are also approved for generalized anxiety disorder, fibromyalgia, panic disorder and similar conditions. Dr. Sean Kane 33:38 Dr. Patel Speaker 3 33:40 my two drug classes that we discussed in the past two episodes were TNF inhibitors, so they're treating a whole slew of auto immune diseases. And I think my focus was a little bit on the daily movement of the brand name HUMIRA. And the second class shouldn't say a class, but an agent was Plavix, which is an irreversible P 2y, 12 inhibitor, which is an anti platelet Dr. Sean Kane 34:03 then my two were the first one was sodenophyll, or Viagra, the little blue pill, and it kind of included some of the other PD five inhibitors, in the fact that they were all kind of a pivotal drug class. And then also levaterraztamer Capra being an incredibly favorable adverse effect profile extensively used in epilepsy. So with that, we'll go ahead and sign off. If you haven't done so already, please give us a five star review on iTunes. We're available at HelixTalk.com we love getting feedback from the listeners in terms of what topics you want to listen to, or what topics you really enjoyed hearing about. So with that, I'll sign off. I'm Dr Speaker 3 34:38 King, I'm Dr. Schuman, and I'm Dr. Patel, and hope you enjoyed the episodes and study hard. Narrator - Dr. Abel 34:44 Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science. For more information about the show, please visit us at HelixTalk.com you.