All right, good morning, everyone. Thanks again for joining us. Gives me great pleasure today to introduce one of my trusted colleagues at Northwestern, Dr. Stewie Patil. Dr. Patil is Assistant Professor of Medicine at Northwestern University. He joined our group. He's now a second year attending. So he joined our group after training at Hopkins for basically everything. So he's become an invaluable member of our group, particularly for me, as we cover Northwestern's Lake Forest Hospital together. He's going to be talking to us this morning about antiarrhythmic drug therapy. So thank you, Stewie, for doing this. And I will turn it over to you. Thank you. Thanks, Nishant. That was a very kind introduction. And I'm looking forward to giving this talk and being a part of your great collection of talks. So I'm going to talk about antiarrhythmic drugs. Admittedly, I think most of us can agree it's probably not the most exciting of topics in the world of electrophysiology. But definitely, I think most would agree that it is a critical topic. Most often, patients don't really meet an electrophysiologist till the question of antiarrhythmic drug therapy comes up. That sometimes is our first point of contact for a lot of our patients. So I'm excited to go into some more detail about the drugs. I'm going to focus this mostly around atrial fibrillation, given that that's the clinical scenario where we most often encounter the decision about antiarrhythmic drugs. So we'll talk about, for AFib, the indications for rhythm control. We'll talk about the antiarrhythmic drugs and really just focus mostly on class 1 and class 3s, which we sort of call the real antiarrhythmics. And then we'll talk about typical guidelines for use for these agents, how to monitor that their associated toxicities, and then whatever important drug-drug interactions we all should know more clinically and as well as for the boards. It's a very common question that comes up. So I think before we talk about the drugs, obviously, some basics that we all are familiar with in terms of when do you start thinking about rhythm control and what do you address before you even get to rhythm control. So obviously, for AFib, if that's what we're going to focus on today, stroke prevention, it's sort of priority number one. You obviously want to assess their stroke risk, what the CHADS-VASc score, and then decide on therapeutic anticoagulation and which patients need indications for that. And then when I see a patient in the clinic for AFib with that first visit, I really stress the importance of risk factor modification and trying to optimize everything we can from a lifestyle and other sort of medical comorbidities perspective. I often tell my patients that everything that I can offer, whether that's anti-rhythmic medications or ablation, really would not be that successful unless we've addressed these other things. So you want to make sure a patient's blood pressures are well-controlled, that if they have a cardiomyopathy or hef-pef, that from a volume standpoint, they're eubolemic and as close to that as possible. If they're obese, obviously, even a mild to moderate amount of weight loss can be very effective in rhythm control, also in affecting the course of sleep apnea. So almost always, I refer my patients for sleep apnea testing, just because over the years, we've seen just how critical a risk factor it is for ongoing AFib. And we know that our anti-rhythmics and our ablations just are not as successful if someone's undiagnosed sleep apnea goes untreated. And then obviously, alcohol is a big risk factor for AFib as well. So talking about that with the patients right at the beginning is important. So three major indications for rhythm control, right? So one is obviously symptoms. So whether that's palpitations, dyspnea, lightheadedness, angina, syncope, heart failure, and these things are happening despite good rate control of someone's AFib, you should start thinking about maintaining sinus rhythm in that patient. Second indication would be if you're unable to adequately control someone's heart rate, especially if they have a tachycardia-induced cardiomyopathy. So maybe they don't have clinical symptoms of AFib, but if their EF is dropped and you can't rate control them well with standard rate control agents, that's another indication for rhythm control. And then there is an indication for patient preference. Some patients just have a strong preference to be in sinus rhythm instead of paroxysmal or persistent AFib. And so those patients you talk to about rhythm control as well. So we'll do one slide on the action potential. Obviously, all of our antiarrhythmic drugs focus on their activities on an ion channel somewhere in our action potential. And so you remember the phases of the action potential. Phase 4 is sort of our resting membrane potential, and it's predominantly driven by potassium channels, the inward rectifier potassium channel. We'll focus on the class 1 antiarrhythmics, which affect phase 0 and our sodium channel blockers or primary sodium channel blockers, and then the class 3s, as a class, almost all inhibit or block the rapid delayed rectifying potassium current in phase 3. And so that's sort of an important target. And we'll talk about how each of the medications sort of influences the action potential in the next few slides. So we all know the Vaughn-Williams classification for antiarrhythmic drugs. So I'll go through this slide briefly and then go into a little bit more detail about each of these. So class 1 drugs are sodium channel blockers. As we talked about, they reduce phase 0, the slope of phase 0, and can decrease the peak of the action potential. Three main types of class 1 antiarrhythmics. So class 1a sort of have a moderate binding and dissociation kinetics, and they can prolong the action potential, prolong acute T in someone's effector refractory period, and some reduction in the phase 0 slope. And the examples of class 1a medications are quinidine, procainamide, and disoperamide. Class 1b sodium channel blockers are sort of, they have rapid kinetics, so they bind on quickly and dissociate quickly, and so sort of think of them as a weak sodium channel blocker. Very sort of minuscule effect on phase 0 slope, and they can actually narrow the QRS, they can narrow the acute T interval, reduce the action potential duration and the effector refractory period. And the medications in this group are lidocaine, myxilatine, and phenytoin. Class 1c's have much slower and sort of stronger kinetics in terms of dissociating once they bind. And in this class is obviously the one that we probably use more often, especially in AFib. And we get a pronounced reduction in the slope of phase 0 without much of an effect on the action potential duration or the acute T interval. And that includes fluconide and propafenone. Class 2 medications are beta blockers. I think we know those very well. So I'll skip ahead to the class 3 antirhythmics, which are primary potassium channel blockers, but some of the medications in this group have multiple class effects. And in this group, we really sort of delay phase 3 repolarization by blocking the potassium channels, that outward current that sort of brings our potential back to resting membrane potential. And so this leads to a prolongation in acute T because of the increase in the action potential duration and the effect of refractory period. And in this group, we've got dafetilide, sodalol, amiodarone, dronedarone, and IV-ibutolide. And then class 4 are the calcium channel blockers. So skip ahead. But, you know, those primarily block the L-type calcium channels and can really reduce sort of automaticity of the SA node and the AV node. So to focus in on the class 1 antirhythmics and how they affect the action potential, I alluded to this in the last slide, but basically the class 1As have sort of intermediate kinetics in terms of, you know, how they bind and dissociate from the sodium channels. And you can get a prolongation of the QRS and a prolongation of the QT with these agents. The class 1B antirhythmics have sort of no effect on the phase zero slope, but can shorten the QT interval slightly. And this is sort of the weakest of the three in terms of sodium channel blockade. And because of its rapid kinetics and ability to dissociate quickly. And then the fleconide-buprefenone class 1C agents, they have the most pronounced effect on that phase zero slope and not much of an effect on the QT interval. And very slow kinetics for these. So these tend to be the potent sodium channel blockers that we use. Just one slide on the class 1As. So quinidine, you know, historically used in AFib or VT, also used in Brugada syndrome and has an effect on the transient outward current at the top of the peak of the phase zero to interface one. It can cause QT prolongation. And with that, there's a risk of torsades and it's actually not dose related in quinidine. Its primary metabolism is hepatic through the CYP3A4 pathway. And about 20% of it is cleared renally unchanged in urine. Procainamide, you know, we use this in VT storm and AFib and where we sort of learn about it in the first time is in pre-excited tachycardias and WPW. This metabolism of hepatic, of procainamide is also hepatic and it gets acetylated to N-acetyl procainamide or NAPPA. NAPPA is interesting. It's got a class 3 antiarrhythmic drug effect. So once procainamide gets metabolized to NAPPA, there's a class 3 effect that can happen as well. And people who are slow acetylators actually develop more toxicity and a risk of drug induced lupus with more NAPPA hanging around. It's a negative inotrope and it also carries with it a risk of torsades primarily through that NAPPA, you know, class 3 effect and prolonging the QT because of the way it's metabolized. And then dasopramide often used in AFib with in patients with hypertrophic cardiomyopathy. It also has a sort of strong vagolitic effect. And so it's anticholinergic. And then in people that you sort of think might have vagal AF, basically, you know, nighttime atrial fibrillation and not see it other times or only during periods of high vagal tone, you could theoretically use dasopramide in that clinical setting as well. It is a negative inotrope and sort of reduces contractility, which obviously, you know, you want in hypertrophic cardiomyopathy. And it also has hepatic metabolism through CYP3A4. The class 1B antiarrhythmic. So this is that group of drugs that have rapid kinetics and dissociation, sort of weak sodium channel blockers. They can be active in partially depolarized myocardial tissue. So in ischemia, you sort of get a slow rise in the resting membrane potential of these cells. And that actually promotes that sodium channel to be in more of a active slash inactive state, which is when these drugs bind. And so it can be fairly effective in the clinical setting with ischemia. We talked about how these drugs shorten the QT without have much of an effect on the QRS. Lidocaine's the sort of first and most used example of these drugs, mostly used for VT and VF. It's got a very high first pass metabolism through the liver. At toxic levels, you know, you get neurologic side effects. So you track levels of lidocaine and sort of end stage of that, you can even get seizures with levels high enough. Alpha-1 acid glycoprotein is an acute phase reactant. And we see it go up in the setting of MI, but also other acute illness. And it actually can bind lidocaine and decrease its bioavailability. So really in situations where there may be an acute phase, you know, illness or a situation going on, you may find that you need more lidocaine than you'd expect to get the same clinical effect. And then in terms of, you know, what to do. So heart failure and shock patients, you actually do need to reduce the dose of lidocaine in those clinical settings and heart failure and shock. You have a reduced, sorry, a reduced volume of distribution. So you need to sort of adjust for that with the lidocaine. And then maxillitine, you know, oral sodium channel blocker, most often used as an adjunctive therapy for VT when we add it on to, you know, in the odor. And it also can possibly block the late sodium channel. So one thing I didn't point out in phase three of the action potential is there's a latent sodium channel that stays open and can let sodium into the cell and sort of lead to sort of, you know, that the plateau of the action potential. And potentially this could be a benefit in long QT3 where you sort of have a gain of function, you know, SCNA mutation and sodium channel that prolongs the QT. And so if you block that late sodium channel with maxillitine you could theoretically treat that. So still need to be a lot of studies on that, but it's a potential therapeutic option in those patients. Class 1C antiarrhythmic drugs. So these are our, you know, one of our workhorses or some of our workhorse drugs for atrial fibrillation. These are the sodium channel blockers with slow association and unblocking kinetics, which means that they can be fairly potent sodium channel blockers. They have a dose dependent decrease in intracardiac conduction. So you can slow conduction of the atrial tissue itself. You can slow conduction of the hysperkinesia tissue. You can see prolongation in the PR and the QRS with not much effect on QT. These drugs do exhibit, sorry, what we call use dependence. And basically at faster heart rates, you block more sodium channels. And the reason for that is more channels, the sodium channels spend more time in the open or inactivated state. So basically phase zero through phase two when the heart rates are faster. So the more time you spend in that open slash inactivated state, you get more blocked sodium channels. And they sort of, you know, dissociate when the channel closes, which doesn't really happen until you get back to, or on the way down to the resting membrane potential. And so you have a stronger effect of these medications at faster heart rates. And so we'll talk about the drugs individually, but this is why we recommend that people be on some avianodal rate control while they're on this so that we don't see sort of the toxic effects of class 1C agents at fast heart rates when someone has AFib or SVT or whatever you're treating with the medication. So mostly used to treat AFib and SVT, as I just mentioned, you can see these agents used for PVC or VT, often really only want it to be in a structurally normal heart. We'll talk about why in a second. You really, you know, people who are coming in with conduction disease issues, whether that's AV block, bundle branch block, you sort of want to avoid the class 1C agents as that can exacerbate those conduction abnormalities. And in patients with left ventricular hypertrophy, class 1C agents tend to be contraindicated, especially in people with LVH, you know, with a wall thickness greater than 1.4, 1.5 centimeters. That wall thickness really just leads to increased transmural dispersion of repolarization. And so it really sort of increases the pro-arrhythmic side effect of these medications. It's contraindicated in patients with structural heart disease. These medications can be a negative inotrope and they can be pro-arrhythmic. So, you know, with the slowing of conduction in the atrium, you can slow someone's flutter down enough to let them conduct one-to-one through their AV node and often with a wide QRS because of the effect of the 1C agent. So this is an example of somebody who got fluconide and you saw a one-to-one, you know, wide complex tachycardia, but it ended up being atrial flutter being conducted that way. So when you hear people talking about class 1C flutters, this is sort of what they're thinking about. And so because of this possibility and the risk of this, you know, we'd recommend that people be on some sort of AV nodal blocking agent at the same time to prevent this from happening. So the trial that has to be mentioned anytime someone talks about class 1C antiarrhythmic drugs is the CAST trial or the Cardiac Arrhythmia Suppression Trial. So this was a study, you know, published in 1991. Patients with prior MI and ventricular ectopy and there were some cutoffs for ejection fraction. If the MI was within 90 days, their EF just had to be less than 55. But if the MI was older than 90 days, the EF was less than 40% to get it to the study. And these patients were randomized to either Encanide or Fluconide. And their primary endpoint was arrhythmic death or cardiac arrest. And you can see in these curves that people who got the Fluconide or Encanide had a much higher rate of arrhythmic death or cardiac arrest. And so for this reason, especially, you know, when we talk about Fluconide and these agents not being used in structural heart disease, we really want to be focused on sort of the potential negative effects in people with coronary disease, especially if they've had prior PCI, prior MI. And it's because of this trial that we avoid use of 1C agents in people with prior coronary disease. Appropriate use of these agents. So these are agents that can be started as an outpatient, which, you know, patients, you know, if you present them options for antiarrhythmic drugs, you know, one of the things that patients like is it's not coming into the hospital to start a medication. So this, you know, you can do these, you can start these as an outpatient. Generally recommend that there be some stress testing prior to starting it, just to make sure there's no evidence of ischemia or coronary disease. Always get a baseline ECG to assess existing sinus node or AV node conduction abnormalities. We do want to monitor the ECG during the initiation phase, as well as for any dose changes. So basically if you, you know, get started on the medication, get an EKG, you know, one to two weeks later, you know, if the QRS duration has increased by 25%, you're supposed to decrease the dose by 50%. And if that doesn't lead to normalization of the patient's QRS, then you really should be discontinuing the one C agent, whether it's Fluconide or Propafenone. You do want to stress people after initiation. You want to get their heart rate up and see if you see that use-dependent phenomenon of the QRS widening with exercise. These agents can increase a pacing threshold. So something to look out for if they have a device and make sure you're checking on, you're doing device interrogations and checking capture thresholds. Again, you've got to make the point of always having these patients on some sort of avian nodal blockade as well. And you do want to avoid it in patients with low EF for the risk of proarrhythmia, as I mentioned, but also these agents do have negative onotropic effects. So you can sort of potentially worsen heart failure. And then again, the same comment about severe LVH, just because it does increase the risk of proarrhythmia, torsades, when your wall is that thick, repolarization can be more heterogeneous and sort of you're putting more of the heart in this vulnerable period where you can have early after depolarizations and potentially induce polymorphic BTVF or torsades. So we recommend not using this medication in people with LVH or severe LVH. So we can move on to the class three. So these are the potassium channel blockers and primarily their effect is in that phase three, the rapid delay rectifier potassium channel. The effect of blocking the potassium channel here, you're gonna sort of prevent potassium from leaving the cell. And so you're keeping the resting memory potential up higher and that sort of prolongs the duration of phase three. And so you get a longer QT with that a longer effective refractory period. These agents actually exhibit the opposite phenomenon. So we saw use dependence with class one agents, we see reverse use dependence with class three agents. Basically this means that these agents block more potassium channels at slower heart rates when more time is spent in phase two and three. And so at slower heart rates, the risk of QT prolongation gets even higher and the risk of torsades gets even higher. And again, for the same reason where you're really spending more time in that vulnerable period where early after depolarizations can happen then you increase the risk of polymorphic VT and VF. And so I'll start by talking about dofetilide or Tecosin primarily used for atrial fibrillation or atrial flutter. No big effects on PR interval, QRS or HV conduction and a minimal effect on the heart rate. Big studies generally have shown less than a five beat per minute decrease in sinus rates in people who get Tecosin. You do need to be admitted as an inpatient for drug initiation because of the risk of torsades and QT prolongation. And in general, we do not start dofetilide on patients with a baseline corrective QT interval greater than 440 milliseconds, or if they're coming in with some conduction abnormalities for QTs greater than 500 milliseconds we wouldn't start dofetilide. Metabolism is 80% renal. And so we really need to dose adjust for creatinine clearance in patients that you're starting on dofetilide. If you're not doing that, you're really just significantly increasing a person's risk of torsades and polymorphic VT slash VF. No major effect of dofetilide on the myocardial contractility and no major effect on a patient's defibrillation threshold. This medication is safe in heart failure and in the post-MI setting. And that was shown in two parallel studies known as the DIAMD studies. So there was DIAMD-CHF and DIAMD-MI. And in both studies, we had about 1500 patients. And just looking at survival in patients with congestive heart failure randomized to either dofetilide or placebo. In the CHF study, they were not allowed to have an MI within seven days of being enrolled. Whereas the MI had happened recently within the last seven days prior to initiation. And these patients were given dofetilide regardless of whether they were having a fib or arrhythmia or whatever. They were just looking at survival with an antiarrhythmic. And so what they found is that in congestive heart failure and in the setting of recent myocardial infarction, really no major difference between dofetilide and placebo in terms of survival. And so that was much different than the CASP study, right? So I think when we compare dofetilide to class Ic agents, much safer in these two clinical scenarios. And you'd be more willing to use it in a patient with coronary disease or a structural heart disease. The sort of other thing they found in the Diamond study is that it's a pretty good anti-arrhythmic. So within that group of patients that got the medication, they looked at who had AFib and who actually converted to sinus rhythm while during the study period. And then if they did convert to sinus rhythm, they sort of looked at what was the patient's probability of staying in sinus rhythm in the two groups. And you could see, you know, dofetilide, you know, patients had a significantly higher likelihood of staying in sinus rhythm if they had AFib and converted on dofetilide to begin with compared to placebo. So pretty good, you know, two, you know, three years out here, we're seeing 60% likelihood of staying in sinus rhythm in those patients. So those were two positive studies for dofetilide. So some drug interactions to be aware of. So really, you know, the ones that come up in our cardiology world, obviously, are verapamil and hydrochlorothiazide. So verapamil increases the absorption of dofetilide as it leads to increased intestinal blood flow. And so that sort of leads to the dofetilide absorption increase. So definitely, you know, you could, with more dofetilide, the higher the risk of proarrhythmia. And so it's contraindicated to be on verapamil with Tecosin and then hydrochlorothiazide inhibits the renal excretion of dofetilide. And so that also increases to unacceptably, or leads to unacceptably high levels of dofetilide. And so that's contraindicated. And then any CYP3A4 inhibitors, which the list is long, can lead to elevated Tecosin levels. And then cimetidine is another one you wouldn't always think of, but it does inhibit the renal excretion of dofetilide. So it increases dofetilide levels as well. So those are some important medications to be aware of, interactions to be aware of. I think on my EP boards, I got at least two, maybe three questions about verapamil and dofetilide and being able to recognize that that is not a good combination and that you shouldn't have someone on both. So important one that comes up clinically, as we see a lot of patients with hypertension, right? But also in preparing for boards, that'll be an important one to remember. So I'll move on to Sotolol. So also it's indicated for AFib. We can also see it used in the treatment of VT or PBCs or VF. Sotolol, it's got a beta blocking action in addition to being a class three antiarrhythmic. So it does cause some negative inotropies. So you want to sort of avoid the use of this in patients with heart failure. This medication also requires an inpatient admission for initiation. And it carries with it. That's because it carries with it a risk of torsades with the risk of QT prolongation. 60% of the torsades events happen in the first three days on the medication and 75% happen within seven days of being on the medication. We talked about the negative inotropy and leading to a risk of worsening heart failure. And it's predominantly renally excreted. So again, another medication that we really have to carefully dose based on someone's creatinine clearance to reduce the risk of proarrhythmia. And then there's, there's dronetarone, also known as Maltac. So this is another class three agent most used mostly for paroxysmal atrial fibrillation or atrial flutter. Could be used for persistent AFib, but you really need a plan to restore sinus rhythm with a cardioversion if you're going to be doing that. And I'll show you why with an interesting study in the next few slides. Multiple ion channel effects, not just class three, but it's got more class effects than that. Dronetarone, as we all know, lacks an iodine moiety. And so the risk of adverse side effects that you see with amiodarone are a lot less with dronetarone. It reaches steady state at about seven days of use. And it's sort of important contraindications are in patients with recently decompensated heart failure, in patients with class four New York Heart Association heart failure, and in people with longstanding persistent AFib. There's no plan to restore sinus rhythm. So essentially people that have met with their doctor or met with their electrophysiologist and have decided to stay in AFib permanently, there's really, it's contraindicated to be on dronetarone due to an increased risk. Some of the important dronetarone trials. So there was the ADHENA trial. This was a little bit more than 4,600 patients in patients with paroxysmal or persistent AFib. The major inclusion criteria were that they were either older than 75, or if they were between 70 and 74, they had one risk factor. So either hypertension, stroke, prior TIA, diabetes, dilated left atrium, or low EF. And they found that being on dronetarone reduced your time to first CV hospitalization or death from any cause as a combined endpoint. That benefit was primarily driven by decreased hospitalizations, as you see in the chart. And to be honest, I know the risk factors here are listed. By and large, most of these patients were paroxysmal. So I wouldn't necessarily jump to putting this on for everyone with persistent AFib. And very few patients actually had an EF less than 40 in the whole study group. But this was sort of one of the positive trials for dronetarone. And then we'll talk about a couple of negative trials. So there was Andromeda, which looked at hospitalized patients with class three, class four heart failure within the last month. And they also had what they documented as a low Walmartian score, but essentially equated to an ejection fraction of less than around 35% or less. Looked at about 600 patients, and this trial was stopped prematurely because the incidence of the primary endpoint, which was all-cause mortality was, as you can see in the chart, much higher in the dronetarone group. And so because of this study, it is now contraindicated to have patients on dronetarone with class three or four heart failure, especially in patients that have had a decompensated heart failure episode in the last four weeks. And if they've had depressed LV function, even more of a reason not to be on dronetarone. Another negative trial for dronetarone was the PALACE trial. So this was a trial done 3,200 patients, all 65 years or older. And then this is the group of people that had sort of six months of longstanding, persistent or permanent atrial fibrillation before being into the, randomized in the trial to either dronetarone or placebo. And you can see in this group, dronetarone increased the combined endpoint, which included stroke, MI, systemic embolism, cardiovascular death, or hospitalization by a significant amount. This trial was also stopped prematurely. And this is the reason that we, it's contraindicated to put somebody on dronetarone if you're not planning to restore sinus rhythm. The risk of all of these major endpoints is just much too high, probably from a proarrhythmia standpoint. Some important drug-drug interactions for dronetarone, verapamil and diltiazam can increase dronetarone levels due to their inhibition of CYP384. Dronetarone itself can actually inhibit CYP2D6, which is a major metabolizing pathway for beta blockers. So through that inhibition, beta blocker levels can be increased just by being on dronetarone. Dronetarone is also a P-glycoprotein inhibitor and an important medication that we sometimes come in contact with, obviously it's Pradaxor, Dabigatran, and that is metabolized through the P-glycoprotein pathway. And so dronetarone can lead to elevated levels of Pradaxa. There's a risk of bradycardia and QT prolongation when patients are on dronetarone and rare cases of severe liver injury or liver failure even. And then we'll move on to amiodarone. So, you know, it's class three, but really has multiple, multiple class effects. So class one, two, and four antirhythmic effects used in atrial fibrillation, atrial flutter, atrial tachycardia, and we see it in BT. It's very lipophilic. It achieves its steady state in about two to four weeks. The terminal half-life or basically the half-life for, you know, from whatever plasma level it is to 50% of that is a long time. So it's about 50 days. So it sticks around in the system for a while. The metabolism is hepatic. There's a three, four mechanism and really negligible renal excretion for amiodarone. It's very well tolerated in patients with heart failure and very low risk of proarrhythmia. So it sounds like the perfect drug, right? Compared to what I've been telling you up until now. But it does have its own toxicities, which we'll get into detail a little bit in a couple of slides here. We, you know, the adverse effects of amiodarone that you want to think about. So bradycardia, really rare torsades. You can see elevated LFTs. Generally, it's a mild increase, but if the LFTs rise more than three times the upper limit of normal, you do want to decrease the dose or just discontinue, especially if it's above that three times the upper limit of normal range. Other side effects can be rash, GI distress, and headaches. When it's given as an IV bolus, you want to be careful about hypotension and monitoring people's blood pressures in that sort of acute rhythm control setting that you're giving it in. And then lots of drug interactions with amiodarone, but the two that I wanted to highlight, digoxin, you want to decrease the digoxin dose by 50% because amiodarone is also a P-glycoprotein inhibitor and digoxin works through that pathway or gets metabolized through that pathway. And then for warfarin, you also want to decrease the dose by 30 to 50% because amiodarone inhibits the CYP2C9 pathway through which warfarin gets metabolized. We'll talk about thyroid toxicity. So amiodarone contains 37% iodine by weight. Basically a 200 milligram dose of amiodarone includes 75 milligrams of organic iodine. And the subsequent deiodination process releases about six milligrams of free circulating iodine per day. And that's about 20 to 40 times higher than the average daily iodine intake in the US. So significant iodine load and it can lead to thyroid toxicities because of that load. We can see hypothyroidism through the sort of Wolf-Chekhov effect, essentially elevated levels of thyroid in the bloodstream and the plasma can sort of lead to blocking of the thyroid's ability to successfully uptake iodine. And so it can reduce thyroid hormone biosynthesis. Amiodarone at the peripheral level and the peripheral tissue can also inhibit T4 to T3 conversion. So that's another way that hypothyroidism can happen with amiodarone. The incidence of hypothyroidism is somewhere between six and 13%. You make the diagnosis by noting an increased TSH and a low free T4. And the treatment for this is either to stop the amiodarone or if you have to be on the amiodarone, you can try giving exogenous thyroid hormone or synthroid. We can also see hyperthyroidism with amiodarone. The incidence of thyrotoxicosis is two to 12% and it's found to be higher in regions where people are iodine deficient. There are two types of thyrotoxicosis. Type one, essentially it really happens in people with prior thyroid disease if they've got nodular goiter or Graves' disease and often can be a very prolonged course. And in the iodine load itself actually leads to accelerated thyroid hormone synthesis in these patients. And if you did a radioactive iodine uptake study, you'd find that the uptake is either normal or increased in this group. In people with type two thyrotoxicosis, you get follicle cytotoxicity with inflammation. It's often transient. And these patients can be steroid responsive. You often see elevated inflammatory markers in this condition and elevated thyroglobulin. And if you did a thyroid uptake study, which sometimes you need to differentiate between type one and type two, you would actually find that the uptake is low or absent in people with type two thyrotoxicosis. The treatment for these, it's a wide range, can be just amiodarone withdrawal. You sometimes need medications to support the thyrotoxicosis, things like methimazole or PTU. And then in some patients they need surgical therapy if the thyrotoxicosis doesn't resolve. There's pulmonary toxicity, low incidence, but can happen 0.5 to 2% in the first year. And after that 0.5 to 1% per year rate of pulmonary toxicity. Sort of different forms of pulmonary toxicity in the acute form. You can see acute respiratory distress syndrome, hypersensitivity, pneumonitis. In this clinical setting, patients can be steroid responsive. In subacute pulmonary toxicity, sort of the clinical features of that are fever and acute dyspnea. And in the chronic form, it's really an insidious dyspnea, nonproductive cough. You can see interstitial pneumonitis. You can see pulmonary fibrosis on imaging. Things to consider is x-ray. And when you look at that, you see diffused interstitial or alveolar infiltrates. And PFTs in these patients show decreased diffusion capacity. And here's an example of an x-ray with those infiltrates bilaterally and CT next to it as well. Other toxicities, there's ocular toxicity. Halo vision is very common. That's a very normal side effect that people get with amiodarone. The more concerning ocular toxicity is if people start to get gradual bilateral vision loss, and that's thought to be due to amiodarone-induced optic neuritis. So obviously patients on amiodarone long-term really need to be followed by an ophthalmologist long-term as well to look for this. And then there's neurologic toxicities, side effects of tremor, ataxia, gait disturbance. You can get proximal muscle weakness from amiodarone as well as peripheral neuropathy. So wide range of toxicities for amiodarone, especially with long-term use. And then just one quick slide on ibutylide. This is an IV medication used for acute pharmacologic cardioversion for a fib or flutter. The risk of torsades with ibutylide is somewhere between two to 4%, depending on what studies you look at. Pre-treating a patient with magnesium, if you're about to give them ibutylide, does reduce the risk of torsades. And it also, if you're gonna, the time where I see this most often is in the setting of cardioversion and trying to improve your rate of cardioversion. And so if you treat people with ibutylide before a cardioversion, it actually does improve their likelihood of conversion to sinus rhythm. When you give it, you really need to keep patients for four hours and monitoring after administration with an ECG or EKG every hour, just to keep a very close eye on their QT interval, as this is a class three agent as well. And the way it's administered is a one milligram infusion over 10 minutes for patients that weigh greater than 60 kilograms. For patients that weigh less than 60 kilograms, it's weight-based dosing, 0.01 milligrams per kilogram. And so this is the last slide. So just a general sort of framework that's taken from the 2014 guidelines for the management of a fib from the AHA, ACC, and Heart Rhythm Society. And, you know, sort of start thinking about patients with a fib, do they have structural heart disease? Do they have a structurally normal heart and what your options are? And you can see that in the group with no structural heart disease, you've got more options. You can think about the class one C agents as long as you're also having them on 18 nodal rate control. Even in these patients, always keep an eye out for LVH and look at an echo and be sure that their wall thickness isn't greater than 1.5 centimeters as that increases the risk of torsades. And that's what this little symbol, the S symbol here is that for really keeping an eye on the LVH for flaconide, propafenone, sotalol, or defetolide. And then if you're at an experienced center and the patient prefers it, you can take someone straight to catheter ablation. But most often we go through a process of trying an antiarrhythmic medication first. And then you can see on the structural heart disease, half of this figure, patients with heart failure, your options are very limited. Really the studies suggest that amiodarone and defetolide are really the only medications that should be considered in that setting based on some of the trials that I talked about. And then patients with coronary disease, obviously you're not going to see class one C agents recommended due to the CAST trial. You can think about defetolide, sotalol, and frenedarone in that group. And then amiodarone obviously can be used for either of these situations as long as there's a close eye kept on possible toxicities and determining how long of course you really need for patients. I think that is the majority of the talk. I know antiarrhythmic drugs is a much bigger topic than that but I tried to sort of hit the highlights and the important things to me. Great, thanks, Duby. That was great. As you said, clinically extremely important for all of us and then very important for the boards. Maybe I'll just ask you a couple of questions. Sure. One is the use of class one Cs for PVC induced cardiomyopathy. Normally we avoid one C agents with cardiomyopathy but they also work very well for PVC suppression. So any thoughts on that? Yeah, I mean, obviously it's an area with very little data but I do, there's a group, the Penn group published this paper a couple of years ago where they really just looked retrospectively at a big population of patients that got one C agents and only came up with 20 total, 20 patients that got class one C agents. And they found that you can really effectively treat someone's PVC. So basically you can see that someone's pre one C agent PVC burn was 36% on average and they got it down to 10%. And it was almost all patients had benefit there and their EF can also improve. And it's only 20 patients, so not a large group. Interestingly, about 20% of the patients had an ICD. So not all of them were protected. So it can be safe in these patients even though their EF is low, if you're fairly confident that it's PVC driven and not some other structural problem, I think it's a reasonable option for these patients, but it really hasn't entered our guidelines yet, but it can be very effective. And interestingly, and I think seven of these 20 patients, they actually had delayed enhancement on cardiac MRI. So maybe you wouldn't necessarily call them totally structurally normal. They did comment in this paper that that delayed enhancement in all seven patients was less than the burden of delayed enhancement was less than 5% and less than 5% scar. So it wasn't a lot of delayed enhancement, but even in those patients, that's what C and D are here that you can drop someone's PVC burden significantly and increase their EF. So it can definitely be considered and potentially an option especially if the patient's a little reluctant to go straight to ablation. I think it's something you can offer. And then another question, that slide you showed us from the AFib guideline says not to use basically any antiarrhythmic except dronadarone or amiodarone if the wall thickness is greater than one and a half, which would obviously make treating HCM patients quite difficult. So any thoughts on other antiarrhythmics for hypertrophic cardiomyopathy? Yeah, so I briefly talked at the beginning about this thought that you could use disoperide with its negative contractility effect, and especially in people with vagal AFib. For hypertrophic cardiomyopathy, that same paper here on the left has a few guidelines. They say, you know, in this class 2A window that antiarrhythmic medications can be useful to prevent recurrent AFib in patients with hypertrophic cardiomyopathy. And the two they mentioned were amiodarone and disoperide. And then also in the category, so less of a strong recommendation, but in 2B, they talked about sotalol, bufetelide, and dronetarone as being possibly considered with a level of evidence of C, so just expert consensus. But I did see this abstract in 2017, so three years after these guidelines, that a group of people retrospectively looked at almost 100 patients with HCM and what antiarrhythmics they got and were they safe and how long did they stay on it. And in general, it seemed like sotalol probably won out there. They had the highest sort of retention rate, also combined with the least people sort of stopping therapy due to inefficacy and, you know, minimal sort of safety events. And I think they're sort of abstract, I don't think it was published, sort of suggested that sotalol may be just as effective and may be okay in people with HCM. I guess possibly maybe due to the beta blocking effect of sotalol and that obviously is an important part of HCM therapy too. So I think the data still needs to be really fleshed out for that group, but I think there are options in hypertrophic cardiomyopathy. And I would say probably either sotalol or dasopramide as a starting point. Okay, great. If anyone else has any questions, feel free to unmute. Otherwise I'm gonna say thank you. Just one for you gentlemen, regarding the quinidine and brugada. So this is really an EP where we need EP specialists to help us. You presented a slide early on saying that quinidine could be used for brugada syndrome therapeutically, but isn't it also sometimes used in the invasive EP lab to induce brugada in people where it's suspected? So could you comment on that? How it's used in both settings or am I misremembering something? Yeah, I'm not sure about using quinidine for sort of brugada testing. We often do a procainamide challenge or edumaline challenge, which can sort of bring out the brugada pattern. With quinidine, you know, the sort of thought as to why it's effective in brugada is, let me pull up the action potential figure, is a blocking of this transient outward current. So it's not necessarily through its sodium channel effects, but by blocking these outward currents, it has some effect in reducing sort of the transmural heterogeneity that people see in brugada syndrome, especially in sort of the RVOT area. And it tends to suppress arrhythmias in that patient and those that it works. But I don't know, Nishat, have you seen people use quinidine for challenging in brugada? No, as you said, normally procainamide in the lab. Yeah. And so thanks for that clarification. And so since they're both 1A drugs, how do you account for the difference in that regard between the quinidine and the procainamide? Well, the 1A just refers to the sodium channel effects, right? I think the difference with quinidine is it also has effects on this transient outward current, which procainamide does not. Thanks.

antiarrhythmic drug therapy

atrial fibrillation

rhythm control

class 1 drugs

class 3 drugs

toxicities

renal function

structural heart disease

AFib treatment