of the board review for this year. We have three wonderful speakers here who will be providing us an overview on pharmacology as related to EP. Our first speaker is Dr. Gestenfeld from UC San Francisco. Just a reminder to everybody, we will take all the questions at the end of the session. We have microphone at the center that can be used, and you can also send your questions through the app. Thank you. Thanks so much, everyone. Pleased to see the few, the proud, the dedicated here hearing about antiarrhythmic drugs at the very end of Heart Rhythm, so glad to see everyone. I do have a couple of questions in my talk, so if you wanna scan the QR code so you can answer the question, take a minute and do that. I know this is, it's called a board review course, but obviously there's not tons of randomized trials about antiarrhythmic drug use, so a lot of it is some of the guidelines, but also it's just some of my practice in terms of how I use antiarrhythmic drugs in my regular EP practice. So start with a question. 52-year-old, CHAZ VAS is zero, AF episodes yearly, last leading to an ER visit due to rapid ventricular rates regarding a cardioversion. It's currently in sinus. His calf showed some mild coronary artery disease, 30% LAD narrowing, but a negative stress test. He's on metoprolol and hydrochlorothiazide. And so if you're looking for the next step to manage his AF, he comes to see you in clinic, you're gonna add apixaban, scheduled catheter ablation with PFA, right? Start flaconide, 100 POBID, propafenone, 300 PO with next AF episode or sodolol, 80 BID. So I'm gonna go, I think I go forward one, and if anyone scan the QR code. And this probably isn't one with an absolute right or wrong answer, it may not have made the cut on the boards, but. Okay, so interesting, 25% go with apixaban, interesting. 50% flaconide. So apixaban, I mean, obviously, we do want to anticoagulate everyone, but I said at the beginning is a CHA2DS2-VASc of zero, right, with an episode a year. So probably not someone you'd need to start anticoagulation yet. Some very enthusiastic folks are ready to ablate him. I'm not sure if that's right or wrong, but one episode a year might be a little early. So yeah, I think this is someone where we might think about pill-in-the-pocket therapy, and I'll talk about that some more, just for rare, but why expose him to 100 Aflac twice a day? He's gonna have side effects every day for an episode that's happening once or twice a year. So I think it's important when we talk about antirhythmic drugs, we don't talk about it much these days, but the real data that shows benefit of sinus rhythm compared to AFib was East AFNet4, and a lot of ablation trials will sort of give this as background, but we have to remember this was an antirhythmic drug predominantly studied. If we look on the left, it was rhythm control versus usual care, most of which was just rate control, and what people got were kind of the common drugs we use, right? Fluconide and dark green, propafenone, a little bit of Amio, a little bit of Dronetarone, and only 10% actually got ablated, 20% by year two, but it's really an antirhythmic trial, and it showed in this composite of death, stroke, or hospitalization, improvement with rhythm control, and no difference in terms of hospitalization, so antirhythmics do still have a role, and even those of us who ablate quite a bit, we all know that we're still using antirhythmics because it's not a 100% fix. With drugs that are out there, I think the 1As, we're really not using anymore. In fact, I was on the boards with John, it was probably 20 years ago, and one of my jobs was actually to get rid of all the questions about quinidine for AFib management, because it really was not used anymore. So I think the 1Cs, fluconide or propafenone, are the class threes. Obviously, Sotolil, dofetilide, Dronetarone, Amio, butylide intravenously. This is in the latest sort of ACCHA guidelines, a structurally normal heart. You've got all these options, dofetilide, Dronetarone, fluconide, or propafenone. I mean, I think for someone with normal heart, no structural heart disease, usually you're not gonna admit them for dofetilide. So typically, it's between fluconide and propafenone, along with avenodal blockade. Amio's a 2A. Sotolil's dropped to a 2B, mainly because of this meta-analysis. So it's important to know in the guidelines. You know, that may be a little bit harsh. I might have dropped Amio down there also. I try not to use Amio, unless there's no other option. Again, if you do have coronary or other structural heart disease, without heart failure, so then Dronetarone is an option. If you've had recent heart failure, then you shouldn't use that. And otherwise, structural heart disease, low EF, you're left with dofetilide and Amio. Again, Sotolil is 2B. I do tend to use a lot of dofetilide in these patients. I think it really works well. You know, the only downside is needing the hospital admission. Again, I think we underutilize sort of acute cardioversion therapy. So intravenously, ibutylite is an option. Sometimes, you know, people, we have to monitor them for at least four hours afterwards. Someone in the unit is not NPO, who is an AFib that can be used for. It's two milligrams over 30 minutes, a milligram over 10, 10-minute break, and then a second milligram. You want to have some magnesium available, not a prolonged QT. You know, amia is often used by the ER, although the acute, you know, it takes time, so the acute effect is not great. You know, procaine is less commonly used. But I think, again, this oral pill-in-the-pocket therapy, so less than 70, 200 a flak, or 300 if you're over 70 kilos, propafenone, 450 to 600, although I'll show you. I often start lower, preceded by an avian odor blocker, right, because we don't want to organize fib into flutter and have it go one-to-one. But even patients, I told the fellows, you know, you come in the hospital on a Friday night, I don't know why the ER admits them, but they're waiting, like, till Monday for a cardioversion. I mean, you can either send them home or give them, you know, 300 propafenone or 450. They may convert and then be able to go home. This is kind of my algorithm. It's important that I think recognizing the guidelines, and I was surprised about this, but they did say as a 2A in patients who are initiating pill-in-the-pocket dosing of flaconidopropafenone with avian odor blocking agents, it's reasonable to start the first dose in the hospital or in a, you know, under observation. And I know we always say that, but practically, it just always seems difficult. I don't know if you guys can do it. If I send someone to the ER for observation, for a-fib, they just get admitted, you know. They won't sit there and watch them for five hours and give them a dose of propafenone. And then I've tried to do this in our EP holding area, but it ties up a bed and all the nurses hate me. So I generally do it as an outpatient if I'm not too worried about someone. So 12 and a half at 25, PO of metope first. After 30 minutes, I'll have them take 150 of propafenone. If their AF persists another hour, they take a second 150, and then they just have them take TID. And it's often worked, so it's just an easy, sort of gentle pill-in-the-pocket strategy that can be used. You know, this drug has all the dosing and metabolism. I'm not gonna go through the whole thing, but a few things to emphasize is that if a patient has advanced kidney disease, it's propafenone, dronetarone, and Amio that are hepatically metabolized. Obviously, some of these folks also have structural heart disease, but if you wanna avoid renal dysfunction, those are the drugs to think about. Again, Amio, as we know, half-life, 14 to 59 days, so it's gonna be around a while. And drug interactions, that's kind of the time these days where I'll use Sotalol. Patients, for example, on multiple HIV meds or cancer meds, Sotalol seems to have the least of the interactions, and Jeannie will talk a lot more about the potential interactions. And Theta-Bacon will talk about pharmacodynamics more, but just to remember, flaccididin and propafenone, as one sees, are generally blocking the sodium channel, so slowing conduction. Defedolide, Sotalol, Ibutelide are affecting repolarization, IKR or IKS, Amio's kind of affecting all the different channels. So sort of my approach in terms of starting these drugs, so normally, you have that structural heart disease, I will get some baseline stress test. I usually get it with imaging. If the imaging is abnormal, I'll get a coronary CTA, and then if they have more than a 50% lesion, either we'll get a cath to sort it out or use something else. If it's normal, the QRS is narrow, they're not super old and bradycardic, then we'll do outpatient initiation, either 50 to 100 BID of Fleck, or Ritamol, usually long-acting twice a day with Metope. I'll usually have them just get an ECG three days after starting the drug, and then we usually see them every six months or so. If they're older, very bradycardic, where I'm kind of worried about it, we might watch them for a couple of days, even for one sees. Structural heart disease, but EF is reasonable, no heart failure, dronadarone can be used as an outpatient. For paroxysmal, I'll probably start with dronadarone. For more persistent forms of AF, I do think dofetilide works well, inpatient initiation, and then we usually see them every six to eight months. If they have significant heart failure, you can't use dronadarone, and then dofetilide, and then obviously there are patients with both renal insufficiency and structural heart disease and heart failure, and then the only option is Amio, which we try to use short-term, but sometimes in older patients, it's an option. And obviously, we do have ablation if drugs aren't working. You know, we see these patients who've had multiple ablations, you know, they've had five ablations, sent for, you know, they're 85 years old, another ablation, or AVJ, they're still having some symptomatic flutters. So that's where, kind of, I consider dofetilide our sort of secret weapon. I think in these folks, you don't want to use 1-Cs, that's slow conduction, because it does tend to perpetuate flutters. But as an outpatient, I've tried dronadarone, but I think inpatient dofetilide works really well. And I've used short-term Amio if a patient's very symptomatic, as a bridge to some other therapy. This is sort of our Waldo slide, but I think it's always good to remind us, we tell patients up front, no drug is expected to be 100% successful. Right, we see these patients, right, they come in, and they're on a, you know, say, adesotolol, and they have Afib once a year, and they fail the drug, and now they try another drug, and then they're gonna be out of drugs soon. So if you're controlled, and you need a cardioversion once a year, that's probably pretty good. And you have to tell patients up front, this isn't 100%, you may have an episode, but hopefully it's gonna decrease the probability of having Afib. And again, occasional cardioversion's okay without necessarily even increasing the dose. You know, what can you expect in terms of efficacy? Sotolol and propafenone, somewhere around 50%. Freedom from symptomatic AF at a year. Defetilide, again, if they can tolerate the 500 dose a little better, about 60%. Again, remember, obviously, the proarrhythmia from defetilide, which is why it has to be started as an inpatient. And then all the drug interactions, which again, Jeanne will talk more about, including grapefruit juice, which can interact with defetilide. Dronetarone actually has a lower efficacy from some of these drugs. From athena and adonis, about 35%. But again, I think if there aren't other options and it had multiple ablations, it is an easy outpatient drug to use. Important to remember the PALACE study. So this was people with kind of more long-term, permanent or persistent AF, more than six months, and they weren't all anticoagulated, so that was not actually required. But it did increase the composite of death stroke or systemic embolism, as well as heart failure, which is why people can't have recent heart failure. But to me, I think it's almost gotten too much of a bad rap. And I do find Maltac and some of these patients on occasion useful. Amio, again, about 60%. We know all the side effects of Amio. I still follow the Amio patients. I know I find a lot of cardiologists that will start Amio but not really follow them very well. And so I still do, again, baseline. I'll get a TSH, liver function, and I'll get a baseline chest x-ray and PFTs. Every, usually once or twice a year, I'll repeat the TSH and LFTs. I don't necessarily repeat the pulmonary function tests unless they're having symptoms. But, and the pulmonary toxicity that we always used to worry about. One reason I like to follow them is you want the lowest dose that works. And people just put them on 200 and leave it there. But if they're doing well, they cut it down to 100. And then I cut people down to 100 every other day, Monday, Wednesday, Friday, 100. And then the side effect risk is much lower. And if it works, that's fine. If not, you can always go up. But I find people just tend to leave them on a higher dose. And again, I think the monitoring, I mean, a lot of them will run into the thyroid abnormalities, right? Hypothyroidism, you can often treat through with thyroid replacement. Hyper is a problem. We really have to stop the AMEO or do something about the thyroid. Yeah, so in this case, again, I think infrequent episodes, Chaz Vaziro just using pill in the pocket, propathinone with a AV nodal blocker is reasonable. He's already on metoprolol. That's why I didn't have to add that in the question. What about PVCs? Let's talk about going to the ventricle. You know, obviously different mechanisms of PVCs. Non-stained VT. But we do see a lot of these patients with idiopathic PVCs, and we all ablate a lot of them. But again, it's not, I often will start, try a beta blocker, it can help. One of my tricks, metoprolol, if it doesn't help, for people, especially with bigeminy, is acebutylol, Sectrol, or for people who say they're too tired on metoprolol, bisoprolol, so sometimes alternate beta blockers can be helpful. You know, maxillotine can be used. I don't find that so helpful alone. 1C's work really well for idiopathic PVCs, and we'll talk a little bit about that. But low dose, like 50 of flecainibid, I find super helpful for people who don't want an ablation or have recurrences despite that. And then class three is sotolol. Again, I've used Multac occasionally. Try not to use Amio unless there aren't any other options. And obviously, ablation, also an option. So this was a nice study from Penn, Dave Frankel, and Matt Hyman. You know, because the question always is, well, someone's got a PVC myopathy, their EF is like 50, you know, that's some structural heart disease, does that exclude use of a 1C drug? How strict are you gonna be? I mean, this is a small group of 20 patients. Six had an ICD, a wearable defibrillator, and if you look at the EF, it was started about 37, but they used flecainide, they used 1C drugs, and you see a dramatic drop in PVCs and improvement in EF. So if they're below 40%, I usually won't use a 1C, but if they're kind of 45, 50, and you want a pharmacologic way to suppress PVCs and idiopathic PVCs, flecainide, I think, is an option with caution. And I'll do some imaging, make sure they don't have scar. But without scar or coronary disease, I think it's okay. And this is the guidelines. So PVCs from the, I think this is ERA, the European guidelines. Idiopathic PVCs, symptomatic, yes. RVOT, just go right to catheter ablation is class one. But if it's, you know, a parahisinus and PAP muscle, one, you might try a beta blocker first, flecainide, and then ablation's also an option. Asymptomatic, you know, greater than 10%, you're following them, greater than 20%. Again, regular follow-up with catheter ablation, possible as a 2B. Sort of similar, just algorithm. Again, less than 5% of PVCs, I just reassure people, tell them, I don't even see them again, don't worry about it. More frequently, you might monitor them. Very frequent, maybe try a beta blocker. And again, rarely ablation, if they get tired of regular follow-up. But often, these do get better over time. Acute VT storm. You know, everyone goes right to Amio. I actually like Lido. You know, the sort of mantras that works best for ischemic VT. But I think it works well for everything, honestly, and it gives you the liberty of, you know, if you want to ablate someone, turning it on and off. Obviously, beta blockers, Amio, Proc, sedation and intubation, epidural, whether it's some sympathetic blockade or sympathectomy, all these are options, so I'm going through quick. In terms of post-infarct VT, you know, guideline-directed medical therapy, exclude cardioid disease, beta blocker therapy, if renal function's okay, I'll often try Sotolol ahead of Amio. Sometimes double therapy, so we can add nixilatine, ranolazine, rarely quinidine, and consider, of course, ablation. I'm just gonna go through this case and not wait for the answer. But this was someone with monomorphic VT, so I think I'm running low on time, and a post-MI, and what do you do? And they were already on Amio, so this is from, vanished from John Sapp's study. And if people are on Amio and got randomized to either increasing the Amio or catheter ablation, if they weren't on Amio, they got Amio. And overall, ablation was better than medical therapy, but people, and that, but that was predominantly in people who were on baseline Amio. So if they're not on Amio, actually adding Amio is equivalent to medical therapy. If they were, that's where, you know, ablation had a clear benefit. So in that case, catheter ablation. Oh yeah, this is kind of a cool study in patients with electrical storm and frequent shocks. They compared two groups, propranolol, 40, followed by 40q6, versus metoprolol. Both were on Amio IV. And actually, interestingly, the propranolol group did significantly better when it comes to events and ICD shocks. So thinking about changing metope to propranolol for VT storm might be useful. There's a study of Proc compared to Amio. And actually, surprisingly, Proc did better in terms of fewer adverse effects and more frequent termination. So something else to consider. And then thinking about the effects of antiarrhythmics on the DFTs. So summary is that sinus rhythm obviously improves outcome in people with recent onset AF. Think about antiarrhythmic drug use. One sees without coronary disease or structural heart disease or best tolerated lower toxicity. Infrequent episodes, think about pill-in-the-pocket with a 1C and an avinodal blocker. 1C is droneterone, Amio is outpatients. Stophetolide always is an inpatient. Sotolol depends a bit on your comfort level. Amio, generally older patients are short-term therapy. PVC is low-dose fluconide works well. Sotolol or Amio for structural heart disease. And for VT and structural heart disease, lidocaine often useful as initial therapy. Proc or Amio if no ablation is intended because it always suppresses the VT. So I hope that's a good quick summary of antiarrhythmics and thank you. Thank you. Thank you, Dr. Gistenfeld for that wonderful review of antiarrhythmic drugs. Our next speaker is Dr. Poole from University of Washington. She'll be talking about drug-drug interaction. Hi, everybody. Thank you for staying for this long at HRS. The circle's going round and round so it's going to open up. Okay, there we go. So, all right. So I'm gonna talk about what you heard, got a bunch of disclosures. So why is this topic important? Well, as you just heard and saw, despite ablation and the other kinds of advanced therapies for arrhythmias, we still use a lot of antiarrhythmic drugs in the management of our patients. And there are limited metabolic pathways and many drugs are subject to the same mechanisms. And this creates plenty of opportunity for adverse drug-drug interactions. And while you may not be able to remember them all, and I certainly don't, it's important to know that serious side effects can occur and when that epic inbox little warning pops up, don't just click and make it go away. Actually, consider, is this an interaction that I just need to be aware of and follow my patient, or should I not use that medication? So we're going to just talk about some basic concepts of pharmacokinetics. So the determinants of drug concentration are predominantly related to these four mechanisms of bioavailability, volume of distribution, metabolism, steady state, and elimination. I'm only going to talk about pre-systemic metabolism if you want to learn about some of the other stuff. You can look at the full talk on antirethmic drugs that's in Core Concepts. I use a lot of cartoons for all of this. It's just, you know, my brain is back in preschool era and I never left. I like cartoons. So pre-systemic metabolism is what happens before the drug makes it into the systemic circulation. So it has to go through the gut or IV, it has to go straight to the liver. So that's what happens there. It finally ends up in the blood is what it's all about. So there are two primary systems that regulate this. One of them you're very familiar with. We've heard about it for decades and decades, the cytochrome P450 enzyme system that's involved in drug metabolism. And then P-glycoprotein, which is really interesting, I at least think it's really interesting. It regulates the absorbed drug. It's a drug transporter. Both are found in the epithelium or the endothelium of the gut, the hepatic portal system, and the kidney. Both are subject to significant genetic polymorphism. And both of them share many of the same substrates, inhibitors, and inducers, just to make it even harder for you. So I like to think of this as passing the gauntlet. So you swallow a pill or you get an IV dose. And what happens is that the drug comes into the portal vein and it has to pass this gauntlet of all of these P450 enzymes, as well as PGP that's busily doing stuff that I'll show you in a moment. And then it's the concentration at the end of when it's gone through the liver that determines things like half-life and toxicity. And there's a term called first-pass metabolism. And that is defined as the concentration is significantly reduced by the time the drug reaches the systemic circulation after one pass through the portal vein in the liver. Well, why is that important? Because that accounts for drugs that are only available IV, like lidocaine, or the requirement for a oral version of that is many, many times higher than what you would need IV. So examples are lidocaine, propranolol, morphine, and tacrolimus. Okay, so some more colorful pie charts. Here are the cardiovascular medications and the common CYP450 isozymes and the substrates. And the isozymes are named based upon their DNA homology. So I have circles around kind of the big three. So let's start over there with CYP3A4. So CYP3A4 regulates predominantly amiodarone metabolism, dronadarone, quinidine, lidocaine, diltiazem, rapamil, ribaroxaban, apixaban, and three of the statins. I don't know if it still is on cardiology boards where they always ask you that statin question, that interaction with amiodarone. So here are the three that, yes, that's the answer, it interacts with amiodarone. And there's a whole bunch of non-cardiac drugs, cyclosporine and a bunch of other things that I took it off for the purpose of today. So then let's go up above the top over to CYP2D6. I think this one's really important because it is the primary metabolic pathway for mexilidine, flecainide, and propafenone, a bunch of the beta blockers, carbadol, metoprolol, propranolol, and timolol, but non-cardiac drugs, oxycodone, and a lot of the antidepressants and mood stabilizer drugs. And this is really important because many patients are now on these medications. We live in a difficult time, it's stressful. People are taking antidepressants, they're taking mood stabilizers. And this can be particularly a problem in the elderly patient. And then there's some other drugs also that you need to know about. Okay, CYP2C9, that's a big boards question. That's warfarin, that's the main metabolic pathway for warfarin, but it also is the main metabolic pathway for a couple other things. Actually many things, long list. Batorsemide and losartan I just have here as examples, and a non-cardiac drug, naproxen. So these are, again, things that you should just know in terms of the big three are where most of the metabolism happens. Now this is a complicated table, but you can have it, it will be available for you. And I'm just putting this together because I'm going to show you and give you the sense of how complicated this whole subject of inhibitors and inducers are. So they're in tabular form here with the antiarrhythmic drugs as well as some other cardiac drugs by 3A4, 2D6, and 2C9. So let's kind of look at this. So if we talk about inhibitors, so what do inhibitors do? They slow down metabolism. What's going to happen is you're going to have increased drug concentration. Increased drug concentration leads to toxicity. So if you look at these inhibitors, amiodarone, dronedarone, didn't I tell you they were substrates? Yep, they're substrates for CYP3A4, but they could also behave as inhibitors. So is diltiazem and grapefruit juice, which was mentioned by Ed. So what do they do? They can inhibit all of the other drugs that I told you about that are substrates for CYP3A4. And again, they can interact with rivaroxaban, apixaban, and these three statins. So I want to talk about the whole point with grapefruit juice. So I think this is also really, really interesting. It's included in the labeling of many antiarrhythmic drugs. So what is it about grapefruit juice that's a problem? It contains these furanocoumarins and flavonoids that can inhibit gut CYP3A4, and it increases the drug concentration of many of the CYP3A4 substrates, and the effect actually can last up to 72 hours. And there's a wide variability of effect, depending upon how much grapefruit juice you drank, the timing of intake to the drug dosing, interpatient variability in CYP3A4 gut activity. And examples of drugs that are affected by grapefruit juice include the calcium channel blockers Dilt and Barapimil, Dofedilide, Amiodarone, Dronenarone, and Quinidine. So this comes up as a big red hazard sign, or whatever you want to call it, on the patient's sun bottles. So it's a real thing. Okay, so going back to the table and CYP3A4. So the other drugs to be aware of that are inhibitors of all of the drugs listed as substrates are the macrolide antibiotics and the azole antifungals, which are also QT-prolonging drugs. So it's a particular problem in QT-prolonging antiarrhythmic drugs, if somebody is given an azole antifungal drug. All right, so let's talk about CYP2D6. So I told you that this is the main metabolic pathway for flecainide, propathenone, mexilatine, several of the beta blockers, as well as for a lot of the antidepressants and antianxiolytics and mood stabilizers. So it's a problem because amiodarone, dronenarone, quinidine, and fluoxetine are inhibitors for all of those other drugs. So again, very important drug-drug interaction. And in addition, sertraline, haldol, citalopram, and paroxetine, which are substrates for 2D6, are also inhibitors for many of the medications that we already talked about. Okay, what about 2C9? So 2C9, again, was warfarin. So amiodarone, of course, interacts with warfarin negatively. Dronenarone does not, right? So you do not have to adjust the dose of warfarin if you're starting a patient on dronenarone. Other inhibitors, again, are fluoxetine, fluvastatin, and fluconazole. Now for board's purposes, inducers are easy. There's only a couple. It's always rifampin. If any test question has rifampin in it, you know it's an inducer. St. John's wort also. And what does that do? That decreases the available drug. So it decreases the effect of the drug because it's going to speed up metabolism. Okay. So I want to talk about genetic polymorphism and give you the example with CYP2D6. So this is an important one to be aware of because about 7% to 10% of whites and blacks are deficient in CYP2D6, which is rarely seen in Asian individuals. It's most important when CYP2D6 metabolizes the parent drug to an active metabolite or the parent drug and the metabolite have different actions that are both active. Substrates include, as you saw, propathenone, flecainide, mexyltene, metope, carbamidol, and propranolol. And propathenone, embolden, because that is the one where this is really an action that you need to understand. So why is that? Well, the main metabolite of propathenone is 5-hydroxypropathenone, which has 10 times less beta-blocking activity than the parent, than the active part of the medication. In extensive metabolizers, which is most of us, that means no mutation, there's less parent compound because it metabolizes quickly into the main metabolite of 5-HP, therefore less beta-blocker effect with its normal elimination half-life of 2 to 10 hours. But in poor metabolizers, 5-HP is not formed or it's slowly formed. So you have more parent compound, which is the beta-blocker effect. So if you use propathenone, I actually like propathenone, it sounds like Ed likes it too, and all you see is that your patient becomes profoundly bradycardic. It might be because they are a person that has this mutation. The effect is greatest at the lower drug doses and the elimination half-life is extended to 10 to 32 hours, and of course it's going to be exaggerated with people who are taking an inhibitor of CYP2D6. So let's switch over to P-glycoprotein. I told you I think this is a really cool thing in the human body. It's a drug transporter, an efflux pump, which controls the amount of drug being absorbed at the barrier in the gut, liver, kidney, and blood-brain barrier. There are multiple substrates and inhibitors. It broadly shares substrates with P450 isozymes, and important substrates are dabigatran and digoxin. Inhibitors increase drug concentration, just like what I told you with the P450 system, and inducers decrease drug concentration, but a completely different mechanism. It is probably the mechanism for the digoxin-quinidine and digoxin-amiodarone-dronetarone interactions as well as dronetarone-dabigatran interactions. So in my little cartoon here, up on top you have this magenta drug, and that's the substrate, and it enters into the bilayer and into this drug-binding pocket with the green arrow. When the portal is open, then what happens is this whole system is ATP-dependent. So ATP binds to unique nucleotide-binding domains, which then trigger a conformational change, and so the drug is just spit back out. So if you can imagine that this is acting constantly along all of these borders in the gut, liver, et cetera, to regulate the drug concentration by reacting to if the drug concentration is too hot to spit more back out into the lumen so it will be eliminated. The drug concentration is too low to allow more to cross that luminal barrier and get into the circulation. So here's little cartoon examples. So what this is, this is the lumen of the gut. I don't know if my arrow, I guess it doesn't show up over there. Well, the lumen of the gut is on the left side, and then if it's, once it's absorbed, it ends up in the blood pool on the right side, okay? So let's talk about dabigatran. So dabigatran etexylate is the parent compound, that's what the patient actually takes when they swallow the pill, and it is subject to PGP transport mechanisms, all right? So let's say we gave a patient dabigatran, and so now at the luminal border it's going to be trying to either eject more back in the lumen or keep more to cross over and get into the blood pool, but if you bring a different kind of drug along, okay, we're going to have a problem. So dabigatran is normally rapidly hydrolyzed to the active form in the gut, which is dabigatran, and once it's in the form of dabigatran, it is not subject to the effects of PGP. So let's bring along a little PGP inhibitor here, such as dronetarone. So what's going to happen here is dronetarone is going to inhibit the ability of PGP to pop drug back in the lumen for elimination, that is, more drug is going to cross over into the circulation that's going to increase the drug concentration and therefore potentially drug toxicity, okay? All right, what about DIG? So digoxin, again, is regulated by PGP, so same sort of basic functionality, and you come along with quinidine, and quinidine is an inhibitor of PGP, digoxin, so the same thing is going to happen. It's not able to regulate digoxin, more is going to cross the luminal border and get into the blood pool, and you can have DIG toxicity because of increased digoxin concentration. All right, so inducers, again, rifampin. So same idea, rifampin is going to act upon a substrate. It's now going to increase the ability of PGP to pop stuff back into the lumen, kind of overactive, and then what is going to happen is you're going to have a decreased concentration of the drug. Okay, so that's how those work. Now, I think it's really important to be aware of the drug interactions with the oral anticoagulants. So inhibitors of CYP450, dronetarone, amiodarone, diltiazem, verapamil, have adverse effects on rivaroxaban and apixaban, so in significant interactions as a blood thing, these can be potentially dangerous interactions. You have to really consider with your individual patient whether or not you should switch them from dilt or verapamil to a beta blocker instead. Dronetarone and amiodarone are also inhibitors for edoxaban by the same system, P450. In terms of PGP, it's recommended to reduce the dose of dronetarone and amiodarone because it's going to inhibit metabolism of dabigatran and potentially increase the concentration of that drug. Amiodarone and St. John's wort also operate by PGP as inducers, decreasing the concentration available to the patient of all four of the oral anticoagulants. Okay, now I just want to mention in closing here, again, this issue of diltiazem and verapamil. So there have been a number of studies now that have looked at the interaction with serious bleeding effects in patients who were being treated with diltiazem and apixaban or rivaroxaban. This is one study of 204,000 Medicare beneficiaries who had one year of follow-up after the start of apixaban and rivaroxaban for atrial fibrillation. They were treated with diltiazem or metoprolol, and the outcome was a composite of bleeding-related hospitalization or death with bleeding. The secondary outcomes were ischemic stroke, embolism, fatal bleeding, and death. You can see the Kaplan-Meier curse for the primary outcome, and diltiazem is in the blue and metoprolol on the yellow. This was a significant difference favoring metoprolol as being a safer medication over diltiazem when using apixaban or rivaroxaban. All right. In summary, drug concentration is directly related to therapeutic and adverse effects. You need to be aware of potential interactions. You need to look at the patient's full medication list, and as I said, pay attention to the EPIC warnings. Always check the hepatic and renal function of all your patients, and use caution in heart failure, because heart failure itself decreases metabolism of many medications. So with that, I'll end, and thank you for your attention today, this afternoon. Thank you, Dr. Poole, for that excellent review of drug-drug interactions. Our last speaker, but not the least, is Dr. Beckerner from Stanford University. She will be providing us an update on pharmacology and arrhythmia management. Thank you very much. I'll try to keep it interesting and mention the more newer drugs, newer antiarrhythmic drugs that weren't mentioned in the earlier talks, so it's a true update, update in pharmacology. And I'll start with the sinus node, then move on to SVTs and atrial fibrillation, then ventricular arrhythmias as the final. And I'm not as technologically savvy as Dr. Gerstenfeld, so I'll take a raise of hands for the first question. What is the mechanism of action of ibridine? Sodium channels, potassium channels, calcium, or this very complicated-sounding hyperpolarization-activated cyclic nucleotide-gated transmembrane channel inhibition? All right. That was the right answer. And I put it there because it might come up like that in the boards, but it's also known as the funny current, and I know all of you are familiar with it. So mechanism of action of ibridine, it's in the sinoatrial node. It blocks... Oh, is it... Oh, yeah. It's red on my screen. Apologies. I think the cursor is not showing there. The intracellular aspect of this channel, which lets sodium in and leaks potassium out, is what that channel does. And when ibridine binds that, it prevents the sodium from leaking in. So in the... Go ahead. Oh, I see. Oh, genius. Okay. I just had to slide it to the next screen I have. So it is effective during the depolarization state of this, when the cells are hyperpolarized, and it slows that. Hence you see the slowing of the actual depolarization, and hence the cycle length or the heart rate. As you see, it does not affect any other phase of the action potential, right? It doesn't prolong the action potential, it doesn't slow down any other cycles, which is not an FDA-indicated use of ibridine. Inappropriate sinus tachycardia, ooh, that is a smart crowd, or heart failure with reduced ejection fraction and heart rate over 70 beats a minute, despite optimal medical therapy. So despite our day-to-day most common reason of using ibridine, that is not an FDA-indicated use of ibridine. So it's off-label for inappropriate sinus tachycardia. I think it's good to know this. I'm not sure if this would be asked in the boards, but it's only indication is heart failure with high heart rates, despite optimal medical therapy. You see here the United States, Europe, as well as the guidelines I summarized here. So it's actually approved for angina in Europe, if it's refractory or intolerant to beta blockers. It is not approved for that in the United States by the FDA. It's approved in both places for heart failure management, if the heart rate is above 70 or 75 beats a minute. And it is not approved anywhere for inappropriate sinus tachycardia. And you might be asked about potentially the guidelines. It's 2A for every indication, angina, heart failure, or inappropriate sinus tachycardia, even though it's not approved. It is mentioned in the consensus statement, not the guidelines, but at least it is there. And if any issues, that is what we code for justifying the use of Ivabredine. These are the approval timelines for some of these things I mentioned. Actually Europe approved it in 2005 for the first time for angina. And they expanded the definition of that angina in 2009. For heart failure, it was about seven years later in European approval. And it was 2015, 10 years behind Europe in approving that for the same heart failure indication in the U.S. And these are some of the trials, some of which did not meet the primary endpoint, hence the challenges in the approvals. Dosing approach, normal starting dose recommended is five milligrams twice a day. But if you're worried of a patient, you know, having more bradycardia than others, I think it's perfectly reasonable to start at the low dose. And you are recommended to monitor these patients and adjust the dose in about two to four weeks. So just like Ed mentioned, amiodarone, don't start it and leave these patients out. I think it's a good idea to bring them back in and find the lowest dose that works for them. And then you can keep the same dose or decrease it as needed. I find it very useful for these patients. These are often, let's imagine, an inappropriate sinus tachycardia patient. They live with this condition. They are very in tune with their heart rates and their symptoms, and they're very smart about this. So as a good experiment, if you're seeing them for the first time in your clinic and putting a patch monitor just to see their baseline, we often at Stanford at least advise them, how about we put the patch on for three days or seven days, depending on how long your patches are, and then start the medication at day five or day seven, and then it's a very clear before and after picture in one assessment that you can do because a lot of the patch monitors summarize the daytime, nighttime heart rate day by day or hour by hour, so you can just use one assessment to get a clear sense of if you're overshooting the dose or if it's ineffective at all. These interactions are very well covered by GNA in the earlier talk, but CYP3A4 is your enzyme here. If there are other drugs on board that inhibit this enzyme, you may have a higher effect of ibabredine. I'm highlighting diltiazem and verapamil because it's likely that those patients might already be on those medications if they're seeing you for inappropriate sinus tachycardia, so it's just a good practice to either discontinue them or maybe start your ibabredine at the lowest dose if they're truly loving diltiazem. It's with some positive effect. Inducers might decrease the efficacy of your ibabredine, and that's sanjoneswort, rifampin, phenytoin that are relatively common. So moving on to SVT. Atripamil can terminate SVTs via which mechanism? Sodium channels, potassium channels, calcium channels, and funicurin. It's an easy one to cheat because it sounds very much like verapamil, and not that it just sounds like it. It actually looks very much like verapamil. You see the only difference in the whole molecule is the sidearm, and even the amount of oxygen are the same, actually just different. Mechanism of action is non-dihydropyridine. L-calcium channel locates very similar to verapamil, but the difference is it has a very rapid onset. Peak plasma concentration is eight minutes. Half-life is much shorter than the existing calcium channel blockers, hence the novelty. For SVT, there have been a couple of randomized trials, NODE1, NODE301, and RAPID. The first one was a phase two trial. NODE1 and NODE301 was a phase three trial of much larger population of the same dose that pretty much, that this randomized enrolled patients with SVT with sustained episodes, so those patients who actually have hours-long episodes that don't self-terminate, and patients, when they have the SVT episodes, they were asked to do vagal maneuvers as well as putting a monitor right as they have the episode, and then they were randomized to either atriopamil or placebo, and here are the results in 30 minutes, 53% reduction or conversion of SVT to sinus as opposed to 35% with placebo. Moving on to atrial arrhythmia management, this is the same medication that is also being used for rate control for atrial fibrillation. REVIRA-201 was published just two years back in CERC A&E, and this was presented three days ago in the Stanford Biodesign by the Milestone Pharmaceuticals Group, so the first study that's already done is atriopamil nasal spray, 70 milligrams, for patients that are physically in the ER coming in with AFib-RVR, and they have a max reduction from the presenting heart rate by 35 beats a minute within an hour of getting that medication, and they achieve, actually, that heart rate within 13 minutes. The effect lasts, so it's not just, for a few minutes, your heart rate is reduced and it's gone, and then the adverse events reported in this trial was mainly just nose spray-related, local irritation, et cetera. There weren't that many bradycardic or serious adverse events. Of course, on the patients randomized to that group, they use much less stiltized metoprol, et cetera, for rate control within that hospitalization or ER visit, and this is how it actually looks. Zero is, you know, zero, a change from the presenting heart rate. Blue is the placebo group, and you see how immediate that response to atriopamil nasal spray is for AFib rate control. They're hitting that minus 30 beats a minute benefit pretty early, and it sustains. This is a three-hour follow-up graph. Rivera 301, as presented by the group, is still in planning. It is meant to be a double-blind, randomized controlled trial of atriopamil, not in the ER, this is not at home, by the patient, self-administered, and with the primary endpoint of a heart rate reduction of around 30 beats a minute. They think about 100 AFib events would be adequate to show any benefit of this drug. Another atrial fibrillation medication that's fairly new, we don't have this at my center, and I wonder how many of you have it. Vernaculon is approved for treatment of new-onset AFib in the European guidelines since 2012. Its action varies with heart rate and resting membrane potential. It has no effect on potassium channels. And the last one is a false answer. It does, it is one of the drugs that is used for pharmacologic cardioversion of atrial fibrillation. Ed summarized these medications in his talk quite well. I just wanted to highlight the efficacy rate of these that is different from what he already presented. So for flecainide and propafenone, cardioversion rates are around 50 to 90% based on this study. Amiodarone, it's much lower, it's around 30 to 70%, and takes much longer, right, six to 24 hours. There's ibidolide, that's the IV alternative, 40 to 50% conversion rate within 90 minutes, and then this is the new drug, 50 to 70% median of eight to 14 minutes. Mechanism of action, it's a multi-channel blocker, but the main effect is through the late sodium channel. And action, just like flecainide, varies with the rate. So if the baseline membrane potential is more negative, the drug doesn't really bind. And if the heart rate is actually, or the atrial rate, I should say, fast affinity, increases and leads to greater blockade and fast onset of action, hence this is not a prevention drug, right? This is a drug that is more useful when people are actively in an abnormal rhythm. But it also blocks the ultra-rapid potassium channel. It also blocks the acetyl-CoA-independent potassium channel, also blocks the ITO. Hence, all these multiple blocks actually help each other in not prolonging the action potential and causing QT prolongation and torsade. So somehow, this kind of a dirty effect on multiple channels helps keep the action potential duration the same. It has been approved for treatment of new-onset AFib since 2012 in the European guidelines. It is not approved in the US by the FDA. This is one little blurb I found online that there is some concerns for serious side effects in the trials, and in 2008, FDA turned it down. In 2019, it was resubmitted and again rejected by FDA due to concerns of hypotension, bradycardia, and ventricular arrhythmias. It is a pharmacologic cardioversion alternative, and the dosing is three mix per KGs in over 10 minutes, and you can repeat it if the cardioversion does not occur. I don't know if this would be asked in the American boards, but I think it might be in the European. There's a randomized controlled trial compared to amiodarone. That was, it's a quite old study, 2011, and quite impressive KM curves. Red is amiodarone, blue is vernaculant-decart. This is the 90-minute proportion of patients who actually convert from atrial fibrillation to sinus rhythm, and if you actually wait, because you know amiodarone acts a little bit slower, there's still quite a bit of difference between the cardioversion rates, even at six hours on this graph. This is a large international study. This is the largest one out there, 1,778 patients. The conversion rate was 70%. It's one of the higher ones of all acute cardioversion studies and these are all the studies using this medication dating 2004, 2010. You see rates around 50% and then no significant safety concerns. These are the more recent ones and some of them are head-to-head comparisons with others. This one I presented with you earlier compared to amiodarone, 50% versus 5%. Compared to propafenone, 93% versus 78%. Compared to ibutylide, 69 versus 43%. This is another flecainide one, 67 versus 46%. Some interesting data available about it that I think it's good to know, at least recognize the name of that one. I'll wrap it up with the ventricular arrhythmia management. Which of the following is not an effect of ranolazine? Late calcium channel inhibition, late sodium, IKR, ITO. ITO, yes, that was the correct answer. So it affects many channels but this gray box is actually the therapeutic range. This is the toxic range. So at toxic range, more channels start getting affected but at the therapeutic range, you see the late calcium, potassium and sodium channel, especially the sodium channel being affected the most here. It inhibits IKR, that which prolongs action potential duration. It inhibits the other ones that abbreviate. So just like the other medication, all these kind of dirty channel inhibition actually keeps the action potential duration relatively stable and protects against TORSAD. This is one of the case series using ranolazine for ventricular arrhythmias. This is 12 patients from Jared Bunch's group with drug refractory ventricular tachycardia and there was a significant decrease in VT episodes and ICD shocks with six months of follow-up. There are actually many studies. There are three randomized clinical trials using ranolazine for VT management. Some were immediately following an NSTEMI. Some are just following ICD ATP treatments, et cetera. They're all very promising looking and there's many observational studies as well, one I shared with you, but there's a few others showing a positive benefit of ranolazine. It is FDA approved for angina in the U.S. in 2008 and arrhythmia management is off-label. I think that's also important to note both for atrial and ventricular arrhythmias. That's it. Thank you very much. Thank you. Thank you, Dr. Bacon. We have a few questions from the audience here. One, let's see. Ed, if the angiogram shows a lesion of 60 to 70%, will you still use? Yeah, I put that in the question, the 30%, because it does come up a lot. Everyone worries about coronary artery disease. If you do an angiogram, you rarely see zero, right? There's usually 20, 30. So I mainly go by ischemia on a stress test, but yes, if it's greater than 50%, I tend not to use 1Cs, but if it's like 20, 30%, I don't. More because concern about potential progression. So more than 50% lesions, I'll usually avoid 1Cs. It's not based on the data. No, fear of lawsuits. You're on a roll, Ed. Do you do regular stress testing on patients on flaconide or forfafanone? I do. Again, it's varied by practice. So I'll do it every other year. And yeah, I just put in the chart, they're due in two years. And then again, similar algorithm to what I put when we started. If the stress test turns positive, I'll either do a CT or cathem or change drugs. But I do do routine stress testing. Let's see, Tina. Why do some insurances cover Ivabradine for IST, but not POTS? Get into the head of an insurance company. I'm even amazed that it's covered for IST sometimes. I truly have a challenge getting it covered for IST. It's a hit or miss. Sometimes peer to peers fail. And even if it's covered, the co-pay could be very expensive for the patients. I've personally not had a different response, IST versus POTS in terms of coverage. I think it's, I've had a bad luck overall for getting it covered altogether, I think. Yeah, this is off label, but both my patients mail to Canada. But maybe with tariffs, that's gonna change. I don't know. But they can get it in Canada. You can also get it in Eastern Europe. Yeah. I've got a patient who's from Romania. Dr. Beykainer, any data on atripamil versus IV or oral diltiazem, not just placebo? And does atripamil cause hypotension? We were on the SVT trial. We were a site on the SVT nasal administration trial. Of course, not that easy to find those patients coming in with acute SVT. There was some hypotension noted in the trial, but not to a serious extent or worrisome extent to prohibit the next trial, which was at home use, right? The 301 trial was patients using it at home. So there weren't any syncope or et cetera noted or at a high rate that was noted. I am not aware of a trial that compares it head to head to diltiazem. Also, brandolazine use, do you use it chronically? Very much. Anybody? I don't chronically for ventricular arrhythmias, but when it's refractory to the other usual things that we try, depending on the type of VT, if flecainide didn't work, sotolol didn't work, or amiodarone didn't work, definitely it's our kind of end line treatment, but we do use it. There was a little bit of rage for using it with dronadarone, I don't use very much of either of those, and it doesn't prolong QT meaningfully. Correct, yeah. Based on the multi-channel inhibition. Anti-drugs are actually good. Yeah. From that perspective. Yeah. Check amiodarone. Let's see, Tina, what mechanism causes atrial fibrillation in patients using ivabradine? I don't think I know. I don't think I know either. What's the mechanism of atrial fibrillation? In the ivabradine use. I haven't heard of it associated with it. I haven't seen it myself. It's a different population than we usually use it in. Yeah. Okay, calcium score. What score would you go by to negate use of a 1C? I don't get a calcium score. Yeah, I was gonna say, I go by stress test and not that. Sometimes, I think people are saying, sometimes they've had a calcium score from a cardiologist for some other reason. But yeah, I don't know that there's an answer to that or any specific number. But again, if it's high, what I might do is get a coronary CTA. And then if you have significant stenosis, then I probably wouldn't use it. But I don't know of a particular score cutoff, but it might make me nervous. If it's 10,000, it's super high, I might think about something else, or just ablating them. I mean, I think it's always good to remember what the long ago CAST trial actually was. I mean, it was 1986. Let's start with that. It was all people who had prior myocardial infarction in 1986. That means they were all transmural infarcts with border zones that were highly arrhythmogenic. And EFs were 40% or less. I mean, it's a very different patient population than we have today that's now been extrapolated. And when it was looked at, the mode of death was highly suggestive that the people who died were having an acute ischemic event. Hence, that's why we do what we do. But I agree. I mean, I do stress testing. And if it's positive or equivocal, I'll do a CTA unless insurance denies it, which they frequently do because they don't understand why you would do a CTA if you just had a stress test. Yeah. Some people do. It's a billable offense. Dr. Gerstenfeld, how are you dosing procainamide for PT store? Yeah, I think, I mean, first thing is you want to be cautious. You know, people with very low EF are obviously real insufficiency where the NAP is gonna build up. So it's generally, you know, if the EF is like 10, I'd be kind of hesitant to use it. Otherwise, yeah, it's generally make per kilogram initial drip over 50 minutes, whatever time it takes, and then dosing it at one or so. I thought it was interesting. I hadn't reviewed it at all that it did actually show better termination and fewer adverse events than MEO. But I would say, again, because of the hypotension during infusion, the time it takes, you know, we don't use it frequently, but it's more in the ones who are responding to other drugs. We must have fewer PT storms in here. And that scares me. Yeah, I use a lot. Well, you end up using a lot because you start running out of drugs to get people, right? Acutely, it's a bit of a challenge, right? Getting it, ordering it from Epic and hooking up an AMEO bag is just too, in a panic situation especially, much easier than procainamide. And that takes about an hour for us to set up. So sometimes, just convenience. Well, Dr. Poole did too good of a job with her lecture. There are no questions. No, it's just boring. Tina, the role of quinidine in recurrent idiopathic VT. Oh, we use that a lot. I'm curious to see what Ed says. But again, running out of options situation, right? Even inpatient or outpatient. That has been another one challenging sometimes to find and fill and there were shortages. But, oh, please. So I have a patient like that, a young girl with an idiopathic VT who had every few years, she goes through this cycle and she gets 60, 80 shots from her ICD. And she ran out of all options that we have on quinidine. And the US manufacturer stopped manufacturing. So she went to Google and was able to get a bunch of Indian, you know, a bunch of her, to get some Indian which is commonly used for malaria. Now, then she bought powders and powders, bags of powdered quinidine and she had heaps of powders. She's filling capsules. Oh, she's mixing it at home. Oh my gosh. She became a pharmacist. Now she's, she's finally found a compounding pharmacy where you mix it in like cookies or something for her and she makes it. It is that crazy. You know, we have a few patients similar to that. I think that works for her. She hasn't had a shock in five years. And no one can induce her map to try an ablation to try and get rid of the VT or? Every time they try to induce it, they can't find it. And she was with me. Now she's in New York. She went to Mount Sinai. The same thing happened. When they tried to induce it, they couldn't get a single PVC, single, they couldn't find it. I've used on occasion, I mean, not a lot, but I've used, I've tried Multac for VT and had some luck on occasion. So they can't get anything else, something else to try. But yeah, I mean, we use Quenaglut, I would say, you know, mainly for short coupled VF when you have PVC triggered VF. Obviously, Brugada works well. She doesn't have the genetic part, but I think she has short QT. No. Okay. Well, that'll be another time. And again, Multac could help. We are out of time for this session. If you have further questions, you come up and ask the individual presenters. Thank you for attention. Thank you for coming. Safe travels, everyone. Thank you.

pharmacology

electrophysiology

antiarrhythmic drugs

arrhythmias

drug interactions

cytochrome P450

Flecainide

Amiodarone

Ibradine

Vernakalant