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Session IV: Noninvasive Diagnosis and Treatment-61 ...
Antiarrhythmic Drugs Part I
Antiarrhythmic Drugs Part I
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Hello, everyone, and welcome to Core Concepts in EP 2022. My name is Jeannie Poole. I'll be talking to you in this presentation about antiarrhythmic drugs, part one. Part two will follow with some example questions. These are my disclosures. We're going to cover mechanism of action, clinical indications and use, some bit about metabolism, and a little bit about drug-drug interactions. Starting with the Vaughn-Williams classification, as you know, our antiarrhythmic drugs are categorized in ways that try to highlight their primary mechanism of action. The Vaughn-Williams classification is what is generally used, although it does have limitations. It is one that is easy to remember and variably places drugs in the correct classification. For instance, the class one drugs are all placed together because their primary mechanism of action is the sodium channel blockade, but they differ by whether they're moderate, weak or strong sodium channel blockers. The class two are the beta blockers. Class three are predominantly potassium channel blockers because they all block IKR, and class four are the calcium channel blockers. The effects on the action potential are different, which is why they're reflected in the classification scheme. Class one drugs all reduce phase zero slope and the peak of the action potential, but there are differences. The 1As also increase the action potential duration, therefore increase the effective refractory period. Class 1Bs have very little reduction, if anything, reduce it slightly. Class 1Cs have a pronounced reduction on phase zero, but no effect on the action potential duration or the effective refractory period. Class three drugs, which are the potassium channel blockading drugs, delay phase three repolarization with a resultant increase in action potential duration and the effective refractory period. As you all know, the class one drugs are quinidine, procainamide, and disylpyramide for the 1As, lidocaine, and maxillitine for the 1Bs. Dilantin, actually, or phenytoin, also is classified as a 1B antiarrhythmic drug. The 1Cs that we use are propafenone and fluconide, and the class threes are diphtherolide, sodalol, amiodarone, denedarone, and ibutolide. Now, getting into the specifics, starting with the class one antiarrhythmic drugs, their properties affect the electrocardiogram, which is very useful for us to be able to look at the therapeutic and toxic effects on the ECG. If you look at the class 1A drugs, they increase the QRS width as well as the QT interval because of their effect to decrease phase zero and to prolong the action potential duration. The class 1Bs, if anything, decrease the QT interval, although not really in a clinically significant way, because they decrease phase zero and shorten the action potential duration. The class 1Cs are the strongest sodium channel blockers and decrease phase zero, but have minimal effects on the action potential duration and don't directly prolong the QT interval. There's another property of the class one drugs that is different between the 1As, 1Bs, and 1Cs, and that's their dissociation kinetics from the channel. So class 1As dissociate from the channel with intermediate kinetics, class 1Bs with very rapid kinetics, and class 1Cs with very slow kinetics. This is important because it has to do with the sodium channel blockers and their use dependence. And use dependence is an effect where it is increased at higher heart rates. It is related to the affinity between a receptor and the drug, and it is voltage-gated and action potential phase dependent. So this little schematic explains how this works. So the drug, say let's, prokaryotamide, for instance, blocks the sodium channel when the channel is open and not when it's closed, obviously. However, it continues to block the sodium channel during the inactive state, and unbinding only occurs during the true resting state when the sodium channel closes. And what that can do is result in a greater drug effect at higher heart rates because the unblocking action becomes incomplete. Now just looking at some facts of the 1A drug, starting with quinidine, historically this was used for both atrial fibrillation as well as ventricular tachycardia. It is now occasionally used in ventricular tachycardia, has become back in favor mostly because of our limited oral options for patients with recurrent VT, especially in patients who cannot take amiodarone. It does prolong the QT interval. It has a set of adverse effects, generally referred to as synchronism, which includes GI and neurotoxicity. It has a unique quality, however, to block ITO. ITO is a potassium channel that opens and closes rapidly, allowing for a brief flow of potassium ions out of the cell, and therefore it is effective in Bregada syndrome and is a medication that is indicated for patients who have recurrent arrhythmias, ICD shocks and symptomatic patients. Procainamide is currently available only IV in the United States. It is used predominantly in VT storm. It does prolong the QT interval. It is used in the U.S. to unmask Bregada syndrome, so patients in whom that's suspected by a type 2 ECG, for instance, can be taken to the lab or under supervision with continuous telemetry. IV procainamide can be infused, and it may unmask a classic type 1 Bregada syndrome ECG. It is also an indication for stable pre-excited atrial fibrillation, so patients, for instance, presenting to an emergency room in pre-excited AF, if they are hemodynamically stable, IV procainamide is the drug of choice. Atrial pyramide is used in hypertrophic cardiomyopathy to decrease left ventricular outflow tract obstruction. So, it has a class 2A indication for this, so it's really not an indication for treatment of atrial fibrillation. However, it can be very effective in these patients, and generally, it would only be given in those patients who have an implantable cardiac defibrillator because it also can prolong the QT interval, and it has significant anticholinergic side effects and can worsen reduced ejection fraction heart failure because it is a negative inotrope. Class 1Bs are lidocaine and maxillotine. Lidocaine is available IV only because of a property called high first-pass metabolism we'll talk about a little bit later. It is used to treat VTVF. It's particularly useful in patients who are having acute ischemic VT and VF. It has no effect on atrial action potential. It does have some significant toxicities that you always need to keep in mind, predominantly CNS toxicity and worsened heart failure, and you really need to follow blood levels when using lidocaine. Maxillotine is available orally only. It is used for VT and treatment of PBCs, often synergistically with other antiarrhythmic drugs. It has no effect on the atrial action potential. It has a unique effect to block the late sodium channel. The late inward sodium channel is a channel where sodium continues to flow through the cardiac channel during the plateau phase, and with gain-of-function SCN5A gene mutations, which is the basis for long QT3, maxillotine has been shown to be an effective medication to shorten up the QT interval, along with another medication, rinolazine. Let's move on to the class 1C drugs. This is fluconide and propathenone. Fluconide is a drug that's been around for a long time. It is indicated for the treatment of atrial arrhythmias. It can also be used for patients with PSVT or PBCs in patients who are not contraindicated for fluconide, which we'll also talk about. It is contraindicated in patients with coronary disease and heart failure. It is a negative inotrope. It can be proarrhythmic, both for ventricular arrhythmias, as well as something called the class 1C effect, where patients are treated with it for atrial fibrillation, and this can promote a more organized rhythm of atrial flutter. It is also a medication that can unmask Brigotta syndrome. It has a unique use in patients with catecholaminergic polymorphic BT, because it blocks the ryanidine receptor. Activation of this receptor results in rapid release of calcium from the sarcoplasmic reticulum stores into the cellular cytosol, and mutations of RYR2 are associated with CPV2, as well as the subtype 2 of ARVC. So fluconide is an indicated medication for patients with recurrent arrhythmias in CPVT. Now propathinone is a drug indicated for atrial arrhythmias. Similar to fluconide, it's contraindicated in patients with coronary disease and heart failure. It is a negative inotrope. risks and can unmask Brigotta syndrome. What's different about it compared to fluconide is that it contains a beta blocker, although it's a weak beta blocker effect, and it is subject to significant genetic polymorphism, which we'll also go over in a little while, because of the differences racially for the CYP2D6P450 isozyme. Both fluconide and propathinone are FDA approved for pill-in-the-pocket therapy with a class 2A level recommendation. So patients who have rare episodes of paroxysmal atrial fibrillation, this can be sometimes a very handy way for them to treat their episodes of AFib and stay out of the emergency room or hospital. The dose of fluconide is 200 to 300 milligrams as a single dose, and propathinone is 450 to 600 milligrams as a single dose. But the first dose needs to be done under medical supervision, which is a problem sometimes. So for instance, if a patient comes into an emergency room and you're wanting to prescribe pill-in-the-pocket, then that is the place to try it for the first time and make sure that the patient has been observed in a monitored setting to make certain that there is no evidence of prorhythmia. And then after that, the patient could potentially use this if they only have occasional episodes. Now, how well does fluconide and propathinone work for acute conversion? This is a nice study that is a summary of a number of other analyses that was published in 2020. On the left, acute conversion rates are compared between fluconide and placebo, and fluconide is in the blue. And at one hour, two hours, three hours, and eight hours of observation, fluconide was significantly better than placebo. When fluconide was compared to propathinone over the same time course, one hour, three hours, and eight hours, overall, fluconide and propathinone were similar, although at the one-hour time point and the three-hour time frame, fluconide had a higher conversion rate. When compared to amiodarone in one set of studies here on the left, there was no difference in a different set of studies. Fluconide was superior to amiodarone for acute conversion rates of atrial fibrillation. This is from the classic Heinlein's article in circulation back in 2002, demonstrating the so-called class Ic effect, or atrial proarrhythmia, where a class Ic drug is given to a patient with atrial fibrillation, and this organizes into an atrial flutter rhythm, usually in a patient who already has had episodes of atrial flutter in addition to atrial fibrillation, and can promote atrial flutter as a sustained arrhythmia, and therefore, the importance of also combining these medications with AV nodal blocking agents. Other class I drugs actually can do this, too. This used to be seen when oral prokinamide, for instance, was available in the United States. One of the greatest risks of this effect is that the antiarrhythmic drug will prolong the atrial cycle length, and this will promote one-to-one atrial flutter, generally presenting with aberrancy, and can be confused in the emergency room for ventricular tachycardia. Now, why are these drugs contraindicated in patients with coronary disease and heart failure? It really goes back to the original CAST trial, which is just one of the most classic trials, and you ought to be familiar with it, of course. This trial enrolled patients with primary myocardial infarction of any ejection fraction unless the MI was within 90 days, and then the EF had to be less than 40%. What's interesting about the trial design is that the patients already had to have been proven to have suppression of PVCs and ambient non-sustained VT on Holter monitoring with the study drugs. The study drugs were inconide and fleconide in CAST I or mericazine in CAST II, and you'll note that propafenone actually was not one of the medications studied in the CAST trials. If suppression was achieved, then the patients were randomized to study drug or placebo. This is the very remarkable Kaplan-Meier curves from the CAST trial, which plots the outcomes for total mortality of inconide or fleconide compared to placebo over the course of days after randomization. This is not months, this is not years, but this is days. Of course, the inconide and fleconide or the active drug was associated with a significant increase in mortality compared to the placebo drug. They went on to then study mericazine, but the mericazine study versus placebo was also terminated early due to excess deaths. When looked at what the cause of deaths were, it appeared that most of them were due to patients who had subsequent ischemic events, with the thought being that inconide or fleconide or medications of this drug classification actually lowered the threshold for the development of ventricular fibrillation in the setting of acute ischemia. There are these important contraindications in both coronary disease and heart failure. The reason for the contraindication in heart failure is that these medications are negative inotropes, so it can worsen heart failure, and also the risk of ventricular prorhythmia increases with decreasing cardiac function. A stress test is often recommended prior to initiating the use of these medications, as well as a baseline ECG, and the reason for the stress test is to screen patients for ischemia. In this day and age, oftentimes a CTA might be used instead of a stress test, but you really need to have documented the patient does not have significant obstructive coronary disease and has no evidence of ischemia. In general, we try to avoid these medications at all in patients with documented coronary disease unless there are absolutely no other options. The baseline ECG is to look for existing conduction system disease, because as I told you earlier, there is a profound effect of these medications on the phase zero of the sodium channel, and you can have predominantly PR and QRS interval prolongation. You really ought to look at this again at steady state, so you can load patients without contraindications as an outpatient, but after about three days, you should repeat the ECG to make sure the patients have not developed a new bundle branch block, and the recommendation is that if the QRS increases to greater than 25%, you ought to decrease the dose by 50%, and if the QRS doesn't then normalize, you should consider discontinuation of the drug altogether. It's not a bad idea to think about putting a patient on a treadmill after the patient reaches steady state just to make certain that they don't have exercise-induced significant QRS widening as a manifestation of the use-dependent properties of these medications. It's worth knowing that both propranolol and flecainide may increase the pacing thresholds, and as pointed out, it's recommended to use concomitant AV node blockers with both of these agents. Let's move on to the class three antiarrhythmic drugs. This includes sodalide, dofetilide, dronedurone, amiodarone, and ibutalide. So we've just been talking about use dependence. What's characteristic of these medications is something called reverse use dependence, and here the greatest lengthening of the action potential duration occurs at slow heart rates with a shortening of the APD with shorter cycle lengths. This short-long-short interval then results in a prolongation of the APD following that long RR interval, leading to instability of repolarization, and this can result in a significant increased risk of QT prolongation, torsadeplant, and VF. Let's talk about sodalol first. These are all, again, just to remind you, IKR channel blocking agents. So sodalol is a mixture of the L and D isomers. L is the non-selective beta blocker component, and the D is the primary IKR blocker. Its indication is for both atrial fibrillation as well as ventricular arrhythmias. Now years ago, it was postulated that just the D isomer might be effective since that was the active component in terms of the potassium channel blocking part of the drug, and this was studied in what was called the SORD trial and published in the Lancet back in 1996. It's sort of reminiscent of the CAST trial, where in this case, D-sodalol was associated with a significantly decreased survival compared to placebo, and the study was terminated early. All the patients in this trial had an injection fraction equal to or less than 40 percent, as well as a prior myocardial infarction. The excess risk in these patients was 31 to 40 percent, and it was noted that an additional risk factor was female sex, which was five times greater than in men. The primary risk of this drug is QT prolongation, with a risk of TORSAD in 1.5 to 2 percent of patients, a risk just about doubles or triples in women. It also can be associated with AV block and beta and bundle branch block, rarely sinus, no dysfunction. It is a negative inotrope, so just need to be aware of that and use it cautiously in patients whose injection fraction is less than 40 percent. Injection hospitalization is required for loading of IV sodalol, or loading of oral sodalol, and IV sodalol is now available for acute conversion and is used by the pediatricians for SVTs for hospitalized patients. These are the sodalol oral loading guidelines. You're probably all very familiar with them. They are based upon a metabolic panel, looking at renal function and electrolytes, as well as measurement of the QT interval. It is contraindicated if the QT interval is greater than 250 milliseconds at baseline in somebody at baseline who has a neural cuirass, and if it's less than that, you can proceed with caution and following this outline, which I'm not going to go through in detail. Moving on to dofetilide, its indication is for atrial fibrillation. Number of safety studies were performed in patients with heart failure, as well as post myocardial infarction patients. These were the Diamond, Sapphire, and Emerald studies. Over here on the right-hand side of the screen, I am showing you the results of the Diamond study, where 1,518 patients with symptomatic heart failure and low injection fraction were randomized to dofetilide or placebo, and there was no difference in mortality using dofetilide compared to placebo. Dofetilide was more effective at suppression of atrial fibrillation in this patient population. Just like Sotilol, it requires inpatient hospitalization for drug loading. It has been used for VT in selective patients, just in clinical use, although that's not its official indication. These are the guidelines for dofetilide loading. They look very similar to Sotilol. Again, you need to have the patient on telemetry, you need to check their renal function and adjust for that if necessary, and if the QTC is greater than 440 milliseconds, it is recommended that you don't use dofetilide. I have a slide here that just simply provides for you the references for the dofetilide safety studies that you might want to familiarize yourself with, and here is a table that looks at the studies and the outcomes in the dofetilide safety study data. IB, ibutylide, also an IKR channel blocker, is indicated for the acute pharmacologic conversion of AF and AFlutter. Ibutylide pre-treatment prior to electrical cardioversion has improved the rates of cardioversion. It has a 4% risk of TORSAD, a 5% risk of monomorphic VT. It requires four hours of ECG monitoring after use, which is why in many hospital systems it just is not practical to do. It is contraindicated that the QTC is prolonged. Correcting hypokalemia and hypomagnesemia first is recommended. Some studies suggest pre- and post-treatment with magnesium as a way to decrease TORSAD risk and increase conversion rates. The dose is adjusted for rates. The dose is given as one milligram, IB, given as a 10-minute infusion for individuals of greater than 60 kilograms, and otherwise it is based upon specific milligram-per-kilogram dosing. So dronetarone and amiodarone, I think sometimes it's just fun to look at the molecular structure of antiarrhythmic drugs, and what I'm showing here is amiodarone on top, dronetarone in the middle, and then the thyroxin molecule. Amiodarone has an iodine molecule, I've circled it here in red. So amiodarone contains 37% iodine by weight, and a 200-milligram dose includes 75 milligrams of organic iodine, and subsequent deiodination releases 6 milligrams of free-circulating iodine per day, which is 20 to 40 times higher than the average daily iodine intake in the United States. So we all know the side effects of amiodarone, we'll go over those, but dronetarone was really made to try to offset some of the significant adverse effects of amniotarum, primarily the pulmonary and the thyroid effects. So the iodine moiety is removed and a methyl sulfonamide moiety was then added to the compound to decrease lipid solubility. So the removal of that and the addition of methyl sulfonamide account for the absence of the pulmonary and the thyroid risks that we see in amniotarum. And here you can see the similarities of both of these structures to thyroxine. So dronetarum, like amniotarum, is a dirty drug. It's a multi-channel blocker, but its primary use as an anti-arrhythmic drug is because it is an IKR blocker. Its indication is for atrial fibrillation. Steady state is achieved at seven days. It does prolong the QT interval and there is a risk of torsad, although it really is not as high as either dulfetilide or sotolol, and can be used as outpatient loading. Like amniotarum can result in liver toxicity, but the risk with dronetarum appears to be higher with some patients in the early studies having demonstrated really significant hepatic failure. There's no pulmonary fibrosis or thyroid dysfunction. There are many important drug-drug interactions, but you do not need to adjust for warfarin. You do need to decrease the dose for digoxin just like with amniotarum. As a black box warning, dronetarum is contraindicated in patients with New York Heart Association class four heart failure, recently decompensated New York Heart Association class two to three heart failure, and it should never be used in patients with longstanding persistent atrial fibrillation with no plan to restore sinus rhythm. Those recommendations come from the primary dronetarum clinical trials, which again you should be familiar with. These are Athena, Andromeda, and the PALACE trials, and at the end of this slide set there is more data from these trials that you can use for your reference. One interesting aspect of amniotarum and dronetarum that was identified from the dronetarum studies was the effect on serum creatinine, which increases slightly with use of both dronetarum and amniotarum, and this is because of its effect on the organic cation transport, but it does not actually change the GFR or actual renal function, but it's a good little trivia piece of information that you ought to know about these medications if you see the creatinine increase slightly. Amniotarum we are all very familiar with. It's an IKR blocker as well as a blocker of many other channels. It's indicated for ventricular arrhythmias. It's the most commonly used drug though also for atrial fibrillation. It's been used for supraventricular tachyarrhythmias, accessory pathway-mediated tachyarrhythmias, and dates back to around the 1960s and 70s when it started to be used in cardiac patients. It is highly lipophilic, which is part of the reason for the pulmonary toxicity. Steady state is reached usually out to about six weeks. The oral loading dose is about 10 grams. It has many drug-drug interactions, so with digoxin, it's recommended to decrease the digoxin dose by 50% and decrease the warfarin dose by 30 to 50%. It can increase the QT and QTC, but it's really uncommon that you see torsad with amniotarum. It can be a little bit of a higher risk with intravenous amniotarum compared to oral amniotarum. So why does amniotarum cause thyroid problems? The risk of hypothyroidism is between 6% and 30% of patients depending upon dose and depending upon how long the patient is treated. So when the thyroid gland is exposed to high levels of iodine, there's a protective mechanism called the Wolf-Chaikov effect. We all have that. That blocks the thyroid gland iodine uptake and decreases thyroid hormone biosynthesis. Usually, the pituitary feedback loop then reaches homeostasis in terms of thyroid hormone after about two weeks, and so the thyroid so-called escapes from the Wolf-Chaikov effect. But if this doesn't happen in certain patients, then this can result in hypothyroidism, and there's a higher risk in patients who have an abnormal thyroid already, such as with thyroid autoimmune disease. Additionally, with more chronic treatment, there's decreased conversion of T4 to T3 in peripheral tissues. The diagnosis is an increased TSH plus a low free T4 as well as clinical symptoms, and the treatment is exogenous T4, or in serious cases, amiodarone may need to be discontinued altogether. Thyrotoxicosis is a much lower risk with amiodarone, 2% to 12%. Type 1 thyrotoxicosis is seen in patients with prior thyroid disease, such as nodular goiter and Graves' disease. This is a problem with accelerated thyroid hormone synthesis due to the iodine load. Type 2 thyrotoxicosis is a follicle cytotoxicity with inflammation. It's often transient and is steroid responsive. The diagnosis is made with radioactive iodine uptake, which will be normal or increased in type 1, but low or absent in type 2. Increased inflammatory markers, such as IL-6 and thyroglobulin, will be identified in type 2. The treatment is amiodarone withdrawal or, in patients who absolutely cannot come off of amiodarone, medical and or surgical removal of the thyroid gland. Amiodarone pulmonary toxicity is the most feared adverse effect of amiodarone. This is a chest x-ray from a long time ago. You should never see a patient that gets to this point without having identified that the patient is at risk for developing pulmonary toxicity. The incidence is 1 to 5 percent. There's a higher risk with pre-existing pulmonary disease. The diagnosis is made off of chest x-ray pulmonary function tests, which are not necessarily specific, but we look at the diffusing capacity or low PO2. Guidelines recommend that PFTs be checked at least once per year. A high-resolution CT scan is more specific by identification of a ground glass appearance. Bronchial alveolar lavage can be performed if it's not clear what the cause of the pulmonary findings are. Classically, you will see decreased macrophages in that procedure. Then biopsies can be done to try to specifically diagnose amiodarone pulmonary toxicity versus other forms of interstitial disease. The pattern on chest x-ray and even CT can be confused with congestive heart failure with bronchiolitis, obliterans, pneumonitis infections, and ARDS. Other side effects that you need to know about are ocular toxicity. So in patients on chronic long-term amiodarone, they will develop halos around bright lights due to corneal deposits. It doesn't otherwise affect their vision. Still in the FDA publications, it will list rare bilateral blindness due to optic neuritis. It's actually uncertain if this is truly an amiodarone effect or not. It's the same patients who are generally at risk for the arrhythmias for which amiodarone will be used are the same patients who are at risk for optic neuritis. In a post hoc analysis of the SCUD-HEP study, we did not identify even a single case of patients in whom this developed. Neurologic side effects are common with amiodarone. You need to be aware of this. Tremor, ataxia, and gait disturbances of peripheral neuropathy and proximal muscle weakness, especially up the upper legs. That one can often be missed as physicians either may not be aware of it or the patient may not report it. It is dose dependent and reversible. Now in finishing up this section of this part of the talk, this is a table that provides for you the pacing and defibrillation threshold changes that are associated with the antiarrhythmic drugs. You should be familiar with these. The next section of this talk is going to focus on pharmacogenetics, drug metabolism, and drug-drug interactions. There are a number of determinants of drug concentration. These are bioavailability, volume of distribution, metabolism, and then steady state and elimination. We're just going to look at a few of the more important aspects of this process. There are a number of factors that can alter the bioavailability of orally administered drugs, such as tablet dissolution and formulation. One of the important medications that you ought to know about where this can be a significant effect is with dabigatran. The patients actually really do need to swallow the capsule. They can't chew it, crack it, or pour it out because that increases the bioavailability and there's a risk of toxicity. Also, physicochemical properties of the drug differ. Gastric and bile pH can be an important factor. Whether or not the drug needs to be administered with or without food, and this is actually really important for rivaroxaban. If it's taken with food, as recommended, it increases the Cmax by 76 percent, which means if patients are taking this on an empty stomach, they probably are not getting a therapeutic effect of rivaroxaban. Then finally, thirdly, bowel bacterial flora can affect the absorption of drugs as well as bowel motility and surface area. I'm just going to quickly mention the volume and distribution. The volume and distribution is defined as the theoretical volume into which a drug is distributed to maintain the plasma concentration at steady state. IV-only drugs like lidocaine have a smaller volume and distribution, which is limited to the circulating blood volume, whereas something, for instance, like amiodarone will have a much greater volume and distribution due to its ability to make its way into lipid-rich organs. The volume and distribution has been greater than the circulating blood volume. The volume and distribution is decreased in heart failure and shock and this is important when using lidocaine because that is one component that can result in lidocaine toxicity. Metabolism, we're going to talk about pre-systemic metabolism. This is a really important part of drug metabolism, really very important in cardiology as well as other disciplines such as oncology. Pre-systemic metabolism is what happens to the drug before it gets into the systemic circulation. This is affected by two very important processes. One is the cytochrome P450 enzymes and the other is P-glycoprotein, which regulates absorption of the drug. Both are found in the epithelium, the endothelium of the gut, the hepatic portal system, and the kidney. Both are subject to significant genetic polymorphisms and what can be really confusing is that both of these systems share many of the same substrates. One aspect of pre-systolic or pre-systemic metabolism is something called first-pass metabolism. This is a property where the concentration of the drug is significantly reduced by the time the drug reaches the systemic circulation. You can think of this as an IV drug, for instance, coming through the portal system and it has to go through this gauntlet of the P450 system and PGP, which is true for lidocaine, which is why it's only available IV because by the time it passes through the portal system, it is completely metabolized. The only way to keep therapeutic drug levels is to continue to give it intravenously. Other medications such as propranolol, morphine, and tacrolimus also undergo high first-pass metabolism. Oral doses are generally high compared to IV doses if the drug is available in both of those mechanisms, IV and oral. This slide shows you the CYP450 isozymes and substrates are predominantly responsible for the metabolism of most of the medications that we use in cardiology. CYP3A4 accounts for the metabolism of dofetilide, amiodarone, dronedarone, and quinidine, as well as diltiazem and borapamil, rivaroxaban, and epixaban. These three statins, simvastatin, atorvastatin, and lovastatin, as well as some non-cardiac drugs such as cyclosporine, terfenidine, and many of the medications used in treatment of HIV disease. Over here is CYP2D6, which is the primary metabolic mechanism for lidocaine, riflocinide, and propranolol. Some of the beta blockers, carbatolol, metoprolol, propranolol, and timolol, and some non-cardiac medications such as oxycodone, amitriptyline, risperidone, and fluoxetine. CYP2C9 is warfarin, phenytoin, torcimide, losartan, and a non-steroidal anti-inflammatory drug, naproxen. So it's, of course, always hard to memorize all this, but I think if you can be familiar with the concepts and be able to at least recognize which of the antiarrhythmic drugs, as well as the anticoagulants, are predominantly metabolized by these isozymes, that'll go a long way for you to not only get answers right if you're taking this course for board review, but also to avoid important drug-drug interactions in treating your patients. This is a table which I won't go through in detail, but one of the important points here is that many of the medications that are substrates for one of these primary isozymes are also inhibitors, and you need to know also about inducers. So I've got the top row in two columns. One of them are the antiarrhythmic drugs, and the other are non-but-important antiarrhythmic cardiac drugs. And if you spend some time looking through this, you'll see how drugs such as amiodarone and ranetarone can be an inhibitor for 3A4, for 2D6, and for 2C9. So it's important to be familiar with this. Now, inducers, there really are only a few that are very important in drug-drug interactions. These are St. John's wort and rifampin, dathomexazone, and phenytoin. So inducers are dangerous because they are going to increase the metabolism of the drug, whereas inhibitors are going to decrease the metabolism of the drug and result in potential toxic levels and adverse effects. So grapefruit juice, we hear about that a lot, and it is often listed in many of the drug labeling of antiarrhythmic drugs. So why is grapefruit juice a problem? Well, it includes tyranocoumarins and flavonoids that can inhibit the gut CYP3A4. It increases the drug concentration, therefore, of many of CYP3A4 substrates, and the effect can last up to 72 hours. There's a wide variability of effect. It depends on how much grapefruit juice was ingested, what's the timing of the intake to the drug dosing. There is interpatient variability in CYP3A4 gut activity. In general, it's probably a good idea to tell your patients to not drink grapefruit juice if they are on medications that use the metabolic pathway of CYP3A4. Examples include calcium channel blockers, diltiazem and verapamil, antiarrhythmic drugs such as dofetilide, amiodarone, dronadarone, and quinidine. Genetic polymorphisms can be very important with many medications. This is a critical issue in oncology as well as psychiatry. For us, in terms of antiarrhythmic drugs, it does play a role with a few of the medications. And so about 7 to 10 percent of Caucasians and African Americans are deficient in CYP2D6, although this is rarely seen in Asians. And it's most important when CYP2D6 metabolizes the parent drug to an active metabolite or the parent drug and metabolite have different actions that are both active. CYP2D6 substrates include propathenone, flecainide, mexilatine, metoprolol, carbadolol, and propranolol. The one drug, however, where this can really have a clinical effect is propathenone. So the main metabolite of propathenone is 5-hydroxypropathenone, which has 10 times less beta-blocking activity. So extensive metabolizes, which is most of the patients, that is, there's no mutation, there is less parent compound, so less beta-blocker effect, and you get more of the class 1 antiarrhythmic drug effect, and the elimination half-life is between 2 to 10 hours. So this is what it is for the majority of individuals. But poor metabolizers, and again that's 7 to 10 percent of Caucasians and African Americans, 5-HP is not formed or it's only slowly formed. So there's more parent compound, so the beta-blocker effect builds up. The effect is actually greatest at lower drug doses, and this can be a problem because the elimination half-life is also longer, 10 to 32 hours, and can be exaggerated with CYP2D6. So what is the clinical effect is that the patient may mostly be having a beta-blocker effect from propathenone and not really the class 1 effect of the drug as an antiarrhythmic. So let's talk a little bit about P-glycoprotein. This is a drug transporter efflux pump which controls the amount of drug absorbed in the gut. It's also found in the liver, the kidney, and the blood-brain barrier. There are multiple substrates and inhibitors, and it broadly shares substrates with the CYP-P450 system. Important substrates, however, to be aware of are dabigatran and digoxin. It's probably also the mechanism for the digoxin-quinidine interaction, as well as the interaction of digoxin with amiodarone and dronedarone. So in this little cartoon schematic, it sort of shows you how this works. So in magenta is the substrate, and it enters into the cell bilayer and into the drug binding pocket, which is this green arrow, when the portal is open. That then triggers ATP to bind to unique nucleotide binding domains, which trigger a conformational change where the drug binding site then presents the drug to the outer extracellular space. And so what this is actually doing is as drugs come in, it'll spit out, if you will, drugs back into the gut to be eliminated in order to try to regulate how much drug is being absorbed. So this is just a little schematic, again, specifically focusing on dabigatran and its drug-drug interaction. And it interacts with amiodarone and dronedarone as the ones you need to be really aware of, as well as rifampin. Rifampin is an inducer, so it's going to decrease the available drug, and inhibitors are going to increase the bile availability. So when patients take dabigatran, it's actually a prodrug. It's dabigatran etexylate, and it undergoes metabolism in the gut through PGP so that after it leaves the gut, it actually is the active drug, dabigatran. But in the gut, as dabigatran etexylate, it is affected by these inhibitors or by these inducers to either increase or decrease bile availability. Once it's undergone its metabolism to the active medication, then none of this is applicable. So this is an effect at the gut level to affect PGP. All right, this is a table that just lists a bunch of substrates, inhibitors of PGP, that you can have for your reference. Finally, going on to the last section on pharmacokinetics, just very briefly talking about half-life and steady state. So here are some common principles. So we know that half-life is the time required for the plasma concentration to fall by 50 percent. So in this cartoon example here, a single dose of a medication is given. It reaches C-max over a certain amount of time, and then the time for the drug concentration to fall by one half is the T1 half. So at four half-lives, the drug is almost completely metabolized. It's not 100 percent, but nearly completely. Now, the AUC, or the area under the curve, is the total amount of unchanged drug that reaches the circulation, and it reflects the exposure to the drug after drug administration. And that is related to side effects, and it is dependent upon the rate of elimination and the dose that is administered. Steady state is defined as being reached when the quantity of the drug is eliminated over X amount of time equals the quantity of the drug that reaches the systemic circulation over the same unit of time. Classic sort of board review questions back in internal medicine, maybe even general cardiology, is that to give a loading dose, you may hasten the time to get to the therapeutic range, but it does not change the time to reach steady state. Here is a table, just to finish up this section, that provides for you the half-lives and the time to steady state for a lot of the anti-rhythmic drugs that we use. And then the rest of this is really additional study resources. There are a lot of tables, and also some of the dronetarone studies are included in terms of the Kappemeier result curves, just for your reference and study. So I'm going to end this section, which is the first part of the pharmacology presentation, and thank you for your time, and hope that some of this information is helpful to you.
Video Summary
In this presentation, Jeannie Poole discusses the mechanism of action, clinical indications and use, metabolism, and drug-drug interactions of antiarrhythmic drugs. She begins by explaining the Vaughn-Williams classification, which categorizes drugs based on their primary mechanism of action. Class one drugs, including quinidine, procainamide, and disopiramide, act on the sodium channels, while class two drugs, such as beta blockers, act on the beta receptors. Class three drugs, like amiodarone and sotalol, block potassium channels, and class four drugs, such as calcium channel blockers, block calcium channels. She also discusses the effects of these drugs on the action potential. Class one drugs reduce phase zero slope and the peak of the action potential, while class three drugs delay phase three repolarization, increasing the action potential duration. Poole discusses specific drugs within each class, their indications, and notable adverse effects. She highlights the importance of considerations such as first-pass metabolism, genetic polymorphisms, and drug-drug interactions in the pharmacokinetics of antiarrhythmic drugs. Finally, she explains concepts such as half-life, steady state, and drug clearance.
Keywords
antiarrhythmic drugs
mechanism of action
clinical indications
metabolism
drug-drug interactions
Vaughn-Williams classification
sodium channels
beta receptors
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