DIP Episode 55 - Cardiac Pharmacology for the USMLE Step 1 (Part 1)

Okay, welcome to the 55th episode of the Divine Intervention Podcasts. My name is Divine. I'm a PGOI One transitional year resident down in Ohio. I will be studying radiology next year. So in today's podcast I'm going to be discussing us some cardio from a college. Basically this is gonna be a series and hopefully by the end you should feel very comfortable with cardio form. My big goal is I'm gonna really emphasize the physiology, really emphasize mechanisms because many of these things like you see people memorize it up the wazoo. It's actually actually pretty easy to understand if you just sort of put your air down and really try to understand things. So to begin a discussion of a cardiac from a college I'm gonna start by talking about the myocardial action potential. Right, and there's five phases to the myocardial action potential. Right, so there's like phase four where you basically have like they're called like leak channels, right? So they're leak potassium channels. They're channels that are permeable to potassium, right? So because they are channels they basically go make things go down the ingredient and we know that potassium is primarily an intracellular ion, right? So the potassium sort of leak out of the cell. They go down the concentration gradient, they leave the cell and that is essentially what establishes the negative resting membrane potential which is usually around like negative 85 millivolts.

Okay, although you can also say that a part of this is also created by the sodium potassium ETP's pump. That pumps are three sodium out of cells and two potassium's are into cells. And then there's a phase zero, right? Where sodium sort of rushes into the cell through fast sodium channels. Okay, again, this sodium ions go down the ingredient because sodium is primarily an extracellular ion, right? And again, that causes the cell to depolarize and then we have phase one which is basically mediated by potassium leaving the cell. Okay, and then we have phase two which is actually mediated by calcium going into the cell and potassium leaving the cell, right? So there you have sodium like I mean potassium leaving the cell which should make the membrane potential negative where you have calcium coming in, we should make the membrane potential positive, right? So that sort of creates a kind of like a still-meater kind of business. And there's actually also sodium, something that's not talked about very often, but it's actually kind of high you to understand this. At least for purposes of the anteriorithmics which I'll touch on some today. In this phase two, there's actually also sodium coming in at this stage and it actually uses very similar channels to the channels that are prey to in phase zero of the myocardial action potential. You'll see why that's important when we get to the class one B anteriorithmics. And then in phase three, right, which is the final phase, right?

It's mediated by delayed rectifier potassium channels. This is basically potassium going out of the cell. The cell is a ripple horizon. And there's some kinds of refractory periods. You sort of want to keep at the back of your mind. I'll see probably the big one is the effective refractory period. Actually, there's sture, there's the effective, there's the absolute refractory period. I'll talk about both. For the effective refractory period, basically, this sort of occurs in phase three of the myocardial action potential. And basically in the effective refractory period, if you have like a strong enough action potential coming down, the cell will fire. And basically, because you're having like a new action potential coming, coming along, right? It's basically this new action potential that's coming along the causes the cell to fire, kind of like in phase three of the myocardial action potential. It's known as an early after depolarization. And the thing is, calcium ions, I will say in general, are responsible for these early after depolarizations. So why is that important? The reason that's important is if you think about a drug like the joxin, the joxin actually places a patient at risk for an early after depolarization. So it's kind of preridmic, right? Because the thing is, if you have an early after depolarization, not all your sodium channels have recovered, right? So you're basically delaying full repolarization if you if you may.

If you sort of think about it that way. And if you delay for repolarization, you kind of stretch out the action potential, right? And I mean, if the action potential is in phase three, and you get like a depolarization, again, the early after depolarization, again, you stretch out the action potential, you increase the length of phase three, right? And that will show up on an EKG as a prolongation of the cutine interval, right? Because the cutine interval kind of revolves around ventricular repolarization, right? And if you prolong the cutine interval, as you'll see as we keep going, that can cause nasty arrhythmia known as a torsad the point, right? So again, to summarize, your purest complex on an EKG relates to ventricular depolarization. It's fast, it's instantaneous. Versus your cutine interval that revolves around ventricular repolarization. This takes a lot more time. In fact, if you look at an EKG, the QRS complex is like super quick versus the cutine interval that is super long. And again, cutine interval ventricular repolarization, QRS complex ventricular depolarization. So some rules you want to take away. If you delay phase zero of the action potential, right, which is the quick part of the action potential, right? Such as by like blocking a sodium channel, for example. That actually does not make much of a difference in the duration of the action potential on an EKG, okay?

The leading down shop on an EKG is that, oh, you're just widening the QRS complex because that relates to ventricular depolarization. Alternatively, if you delay phase three of the myocardial action potential, when you essentially have an inventricular repolarization, which we know is a longer process proportionally compared with ventricular depolarization, the duration of the action potential on the EKG will actually increase a lot, okay? And on an EKG again, that will show up as a prolongation of the cutine interval. So, again, if you do not have the ability to block potassium channels, you will not prolong the action potential duration. And then the second refractory period is the absolute refractory period, basically, for new action potential comes down during the period of the cell. The cell will not fire. So now that we've talked about the myocardial action potential with five phases, let's talk about the peacemaker potential, which has three phases, okay? The peacemaker potential has three phases. Basically, there's a phase four, a phase zero, and a phase three. In phase four, you basically have something known as a funny current, okay? It's like a mixed sodium and potassium current. Basically, there's funny currents, essentially, give cells a property, known as automaticity. What does automaticity mean? It just means that these cells have the ability to depolarize on their own, right?

They can sort of like slowly depolarize on their own towards a given potential and then the cell will fire, okay? So if you sort of think of it as a slope, like, oh, you're streaming off that slope for the cell to depolarize, the thing is you want to be able to analyze those things in the context of the sympathetic and the process and pathetic nervous system, right? So for the sympathetic nervous system, it actually makes the heart go faster by making that slope for the funny current for phase four steeper, okay? So it sort of like increases that slope, makes it much faster, right? Versus your power and pathetic nervous system. It actually makes the heart beat a lot slower, okay? By making the slope of phase four, right? That funny current slope less steep, okay? So it basically kind of slows down the heart, okay? And then after phase four, we have phase zero. This is actually mediated by calcium and it's mediated by calcium running, sort of rushing into the cell, right? So that will cause a depolarization. And again, this calcium rushes in through L-type calcium channels. Please don't confuse L-type calcium channels with the T-type calcium channels that are blocked by the drug use for up-son seizures, right? Ethosoxamide. Remember up-son seizures, like the three per second or three hurts a spike and wave pattern. You can, the drug of choice for the treatment of those kinds of seizures is ethosoxamide. And then there is phase three, which is mediated by potassium, okay?

That basically causes repolarization of those of those cells. Now, the first drug I'll talk about here is Iverbredin, right? So it's IVA, BRA, DIN. This drug is actually fairly new. It inhibits the phonysodium channels, again, which is part of phase four, right? In pacemaker cells. So again, very high yield. It inhibits the phonysodium channels in pacemaker cells, right? So it inhibits phase four of the pacemaker potential. And basically, by doing that, right, to basically decrease the activity of SA and AV nodal cells, right? So your cyanoatril and your atroventricular nodal cells. So your heart rate actually decreases. However, it's actually super, super high yield to know that this drug does not decrease the force of contractility of your heart, right? So sort of contrast this with a beta blocker, for example, a beta blocker. I'll talk about those probably in a different podcast. Those are the class two anti-ritmics, right? Beta blockers, right? They basically dumb down your sympathetic nervous system. So they decrease the slope of phase four of the pacemaker potential, but they also decrease cardiac contractility, okay? So beta blockers and negative chronotropes and ionotropes. I've a burden is a negative chronotrop, but it actually has no ionotropic effects, right? So why may this be useful? I mean, kind of think about this. What could me for a second here? If you have a patient that has severe heart failure, right? And they have like 15% ejection fraction.

So you just ejection fraction, essentially in the toilet, right? If you give them a beta blocker, the ejection fraction will decrease even more, right? Because beta blockers decrease contractility, the negative ionotropes. Well, think about it. If you decrease the heart rate only, the only thing you brought down was the heart rate and you don't affect contractility, basically like the way I've read in works, then the time you spend and dastily will actually increase because the heart is going slower, right? And if the time you spend and dastily increases, your end dastolic volume would increase. And if you think about the Frank Stalin principle, that will actually increase your stroke volume, okay? And if your stroke volume increases because cardiac output is heartbeat and stroke volume, your cardiac output will increase as well, okay? So again, I've a burden is a negative chronotrop, but it has no ionotropic effects. So let's jump to the antherithmic, right? So we have the class one antherithmic, these are the sodium channel blockers. So again, the basically delay phase zero of the myocardial action potential. And again, on an EKG, you see that it's a widened QRS complex, right? Because the QRS complex relates to ventricular depolarization. And the thing is, again, if your block sodium channels, you do not necessarily prolong the action potential duration.

Because again, most of your time, if you look at the cardiac cycle, most of the time is spent in ventricular depolarization on an EKG, on an EKG, okay? So again, because it's been most of your time in repolarization, basically the QT interval, if you just, if all you did was to block sodium channels, the action potential duration will not change by much, okay? Well, contrast this with like your class three antherithmic, right? These are potassium channel blockers, right? So the delay phase three of the myocardial action potential, right? And basically, you capture this on an EKG with a prolongation of the QT interval, right? And as I said earlier, a prolonged QT interval can lead to something known as a torsada point. It's a pretty federal arrhythmia, although that strided with magnesium. So again, I'll reiterate this point again, it's super, super high you to understand. If you do not have the ability to block potassium channels, you will not, again, very high yield, you will not prolong the action potential duration. So let's visit this class one antherithmic in a little more depth, okay? So again, the action on the myocardial action potential, there's three classes here, there's class one AB and C. On the class one A, we have drugs like a disopera mite, right? Quinidine and perquinamide. So the numonic, there's double-quarter pounder, okay?

So disopera mite, quinidine and perquinamide, the block sodium channels, but actually also have the ability to block potassium channels. And then after that, we have the class one B agents. The numonic here is a let us, let us, may or tomato, okay? So like a lidocaine, mixillatin and another drug known as tokinite. Although I want you to sort of put an extra drug in there, phenitoin. I think of phenitoin also as being a class one B antherithmic, okay? So the thing is, these class one B drugs, they block phase two sodium channels, okay? They block phase two sodium channels, and those phase two sodium channels, they are known as the window channels. Remember, I said that for phase two of the myocardial action potential, we have sodium rushing into the, I mean, we have potassium rushing out of the cell, we have calcium rushing into the cell. We sort of create a steel mate, but in addition, we also have sodium rushing into the cell during that phase two, okay? So your class one B drugs, they are especially good at blocking phase two of the myocardial action potential. And by blocking these sodium channels in phase two, those window channels, you basically make it easier for potassium to win the battle as potassium can rushes out of the cell, okay?

So this is actually why the action potential duration decreases with your class one B antherithmic, because again, if you sort of think about like a tug of words like, oh, you have sodium and calcium on one side, and you have potassium on the other side. Potassium is coming out of the cell, sodium calcium going into the cell. If you take out one of the guys, if you take out the sodium by blocking those window channels, the sodium doesn't rush into the cell anymore, so that means potassium wins the battle, so a lot earlier, so that you can just go quickly into phase three, okay? So this is why your class one B agent actually decrease the myocardial at decrease the action potential duration. And then the class one C antherithmic, you can use the numonic like fries, please, so like flake canite, propafe known, there's another drug known as enquinite, enquinite is also a class one C antherithmic. These drugs I think of them as the purest sodium channel blockers, okay? So they have no effect on the action potential duration. So again, work with me here, the class one A agents, they block sodium channels, so they're widening the QRS, but they also block potassium channels, so they'll prolong the cutie interval. The class one B agents, they block sodium channels, but one sodium channel that they're particularly specific for, at the sodium channels in phase two of the myocardial action potential.

So by blocking those sodium channels as I painstakingly explained a few seconds ago, they actually decrease the action potential duration. And then for the class one C drugs, they have the pure sodium channel blockers, they don't have any other drug description, all they do is that they block sodium channels, okay? So if you're again looking at the gradation of things, the action potential duration is increased by class one A agents because they have potassium channel blocking abilities, no effect whatsoever in the action potential duration is the purview of the class one C agents, okay? Because they again, they have the purest sodium channel blockers, they essentially do nothing else. And then if you're looking at decreasing the action potential duration, think about your class one C drugs, okay? Because they block those phase two sodium channels, sodium channels, right? So like the windows sodium channels. And again, all these drugs because they have sodium channel blocking activity, they widen the QRS interval, okay? Now, let's talk about another relatively complicated concept with these class one drugs. The thing is, a sodium channel can exist in, let's say one of three states, okay? A sodium channel can exist in a resting state, okay? This is like what you see in phase four of the myocardial action potential, at that state it's ready to fire, okay? Now, sodium channels can also exist in a state known as the open activated state, so they are open and they are working.

That's more phase zero, right? Of the myocardial action potential because it's those sodium channels opening that makes sodium rush out of the rush into the cell to promote depolarization of the myocardium. And then the third state that a sodium channel can exist in is the closed in activated state, so it's closed and sodium ions cannot run through that channel, okay? So, resting state that's phase four of the action potential, so that's myocardial action potential, resting open activated is phase zero, okay? Of the myocardial action potential and then closed in activated is phase one and two and three of the myocardial action potential. So, here's the deal, why am I going through all this pain? To explain this, the reason I'm going through all this pain is that sodium channel blockers can actually block sodium channels best in phases zero, one, two, and three of the myocardial action potential, okay? The thing is the sodium channel blockers, your class one agents, are not very good at blocking sodium channels effectively in phase four of the myocardial action potential. So, again, I'll reiterate this, sodium channel blockers, your class one anterior mix, they're very good at blocking phases zero, one, two, and three of the myocardial action potential, right? So, those sodium channels that are working in those phases, but in phase four of the myocardial action potential, your sodium channel blockers are not very effective at blocking those sodium channels, okay?

And the thing is, if you're going through phases zero to three, right? Basically, the sodium channel is not available to do stuff, okay? It's not available because those sodium channels are basically inactivated at that spot, right? So, if you think about it like phases one, two, and three, the sodium channels are closed, they're inactivated because the cell is in a refractory period, if you may, but in phase zero, right? The sodium channels are already open, right? So, it's not like you can like force them open again, right? So, when you're in phase zero, one, two, and three, okay? Your sodium channels are set to be in use, okay? So, if you're in phase zero, one, two, and three, sodium channels are set to be in use with respect to the myocardial action potential, but if you're in phase four, the sodium channel is actually available, right? It's like, it's basically in a resting state in phase four and it's ready to fire because essentially all the sodium channels have recovered, essentially all the sodium channels have recovered. So, one of the concepts I want to establish is that the faster your heart goes, right? So, if your heart rate is faster, you actually spend more time in systole, okay? And I will encourage you to sort of diagram this out, just sort of like look at like the cardiac cycle and see like, oh, wait, if my heart is going faster, will I spend more time in systole or dastole? And the answer is you actually spend more time in systole, right?

So, if, and we said that when the heart is contracting and the heart is in systole, right? A lot of your, if you're basically spending a lot of time in phase zero through three of the myocardial action potential. So, we said, we already established that sodium channel blockers, right? The love binding to sodium channels in phase zero, one, two, and three, right? So, when those sodium channels are in use and not available for firing anymore, okay? So, that is the term, that property that I just described is what creates the term known as use dependence with the sodium channel blockers. Sodium channel blockers are used dependent because again, they bind to a heart that is more in tune with with systole, okay? That's more in tune with systole, right? So, if a heart is going really fast. So, one thing I want to say is that if you understand this use dependence ability, right? Then you can see a property I'm going to talk about right now actually. And the thing is your class one age drugs, your class one B drugs, your class one C drugs, they have very different abilities to unbind from the sodium channels that they have bound to and blocked, okay? So, let's talk about the class one C drugs. The thing is the class one C agents, right? So, like your flaky night and propa phenomenon, the unbind very slowly, very, very slowly from the sodium channels that they have blocked, okay?

And the thing is these drugs because they unbind very slowly, they demonstrate the greatest sodium channel use dependence, right? So, let's think about this for a second, work with me here. If your heart is building really fast, right? So, if your heart rate is like through the roof, right? These class one C drugs, they have not completely unbind from the sodium channels that they have bound to and blocked, right? Because again, remember that they unbind slowly, right? So, they've not completely unbound before the next depolarization. So, that comes along, right? So, because they're not completely unbound, right? By the time you enter the next cardiac cycle, the block that these drugs exert on myocardium on the sodium channels of myocardium, begin to accumulate if you may, right? Because it's like, oh, you blocked the sodium channels because really the right thing you're supposed to do as a drug, as these drugs is you're supposed to bind and then you unbind, you bind and then you unbind, you bind and then you unbind. Well, these drugs, let's assume your heart is going really fast, they're all bind, but before they unbind is like, your heart has depolarized and repolarized again. And in that repolarized state, those use states, right? So, like, phase is zero through three of the myocardial action potential. The class one C drugs is like, oh, well, we almost spent no time in the depolarization phase. So, I might as well just chill on this, repolarize the sodium channel, right?

Because that's its preferred binding configuration. So, if that happens, you keep accumulating blockade of your sodium channels and if you keep accumulating the blockade, right? You keep letting your sodium channel sort of stain that state where they're in use and not available for depolarization. If the block accumulates, you'll get to a point where you basically have blocked all your sodium channels. I mean, you probably will not reach that spot, but let's assume theoretically, read that spot where you've blocked all your sodium channels. Then your heart will basically not contract anymore because there's nothing eating depolarization and the person can go into a systole with that, okay? So, because these are your class one C agents on bind very slowly, they're blockade of sodium channels can accumulate very quickly, especially at very fast heart rates. Because at fast heart rates, you're spending a ton of time in systole. If you're spending a ton of time in systole, you're spending a ton of time in phases zero through three of the myocardial action potential, which is actually the preferred binding spot for your sodium channel, for your sodium channel blockers. That's why they're known as use dependent agents. So, your class one C drugs demonstrate the most use dependence because they're on bind slowly. And now, basically, like, talked about this in many different ways, but it's an important concept to understand.

Especially for those of you that are going into internal medicine or cardiology in the future. Okay, and then your class one A agents, right? So, they have like intermediate on binding abilities, right? So, they basically demonstrate intermediate, intermediate, sodium channel use dependence. And then your class one B drugs, right? Your lidocaine, mixulate in and took in, right? They're on bind very quickly, okay? And because they're on bind very quickly, they demonstrate the lowest sodium channel use dependence. Now, these drugs, they're basically used to treat bad tachy arrhythmias, right? So, like, V-tack, right? The thing is, they will not work if the person has a bradycardia, right? Because if you have a bradycardia, you're spending relatively more time in phase four, right? Where essentially, these sodium channel blockers cannot work because they'd rather bind to phases zero, one, two, and three, okay? But if you start getting a tachycardia, right? Then these drugs start to work really well, right? Because, again, you're spending more time in phase zero through three. Your class ones, these drugs, they work very well, right? Because they have that high sodium channel use dependence, okay? But again, don't forget that they also have the largest risk of death due to the accumulation of the effects, right? Which can, again, ultimately to assist, or as a You Tube cartoon, I watched recently, assist, okay?

It was like an ortho-person arguing with an anesthesiologist, but that's a story for another day. Okay, so back to this. So Wolf Parkinson-White Syndrome, right? Basically, the pathophys involves having something on the bundle of Kent that allows signal, right? The action potential to travel from myocardial cells in the right e-trum directly to the pomeocardial cells in the right ventricle, right? So essentially bypass the AV node, okay? Which is like a natural slowdown mechanism for the impulses that are flowing from the right e-trum to the right ventricle. So how do we treat WPW? Which is a prokina mind? So prokina mind, remember, right? It's a class, it's a class one A anti-rhythmic, okay? It's the drug of choice for treating WPW syndrome, because it suppresses myocardial contractility, I mean myocardial excitability, okay? So that it makes going through the bundle of Kent a lot less favorable than going through the AV node, okay? But one high-o thing you want to know about prokina mind is that it's in patients that are slow-assetal leaders, it's actually associated with something known as drug-induced lupus, okay? Don't forget the association of drug-induced lupus with anti-histona antibodies. And here's one very commonly tested exam factority. If a patient has WPW, right? And they have a fib, and you give them a beta blocker for some reason, right? That's actually a pretty bad decision, right?

Because in WPW, that bundle of Kent, that bundle of Kent is like wide open, right? And your AV node, if a patient had like a fib, right? Then usually for a fib, right? You give an AV node blocker, like a beta blocker, for example. But the thing is if a patient has AV and WPW, you give a beta blocker, you block the AV node, you're not blocking that bundle of Kent. And even if you're doing anything, you're essentially increasing flux through that bundle of Kent. And that can cause some very nasty aridmias and cause a sudden death. So if a patient, the big thing you want to remember is that if a patient has WPW, don't give them anything that can block the AV node, right? For example, you don't want to give them a beta blocker, you don't want to give them a non-dihydroperidine calcium channel blocker, right? So like, very up a mill delta ism, you don't want to give the joxen, right? So the joxen is an inhibitor of the sodium potassium ATP espomp, but it's also a muscarinic receptor agonist, okay? So it can slow down conduction through the AV node because it activates the parasympathetic neurons that modulates the AV node. Another thing that can also slow down conduction down the AV node is adenosine, okay? So just so they keep that at the back of your mind. That's why it's used to treat... That's why it's used to slow down the heart relatively quickly. If a patient has a... If a patient has like AFIP, right? It's basically like an outroot of... What do I want to say?

Yeah, it skipped my mind. I'm going to keep going. Hopefully I remember it at some point. So our jump to quinidine. quinidine is one of the class 1 A agents. It's a sodium channel blocker, but the super high-yield thing you want to know about quinidine is that it's a muscarinic receptor antagonist, okay? So because it antagonizes muscarinic receptors, it actually increases your heart rate, okay? And because it has anti-colonersic activity, basically, right? It can increase your risk of delirium. So you don't want to give this to the elderly, right? And another thing is that it can actually cause constipation and urinary retention again because of its anti-colonersic effects, right? And one other thing you can do is it can cause some illness, synch anism. Synch anism. That's just one high-yield thing. You want to be able to associate with quinidine. Synch anism. Synch anism, synch anism, okay? Synch anism. That involves like tenedus and like some other neurologic issues that can arise with taking a quinidine. And the thing is quinidine, if a patient like absolutely needs to take quinidine, we don't want to speed up their heart rate, right? So that you don't get like all this badness with use dependence, you can actually give them the joxin because remember the joxin has most chronic receptor agonist activity. So you can sort of counter some of those nasty, nasty side effects that go along with a quinidine, okay? Very high-yield to know that.

So I'm going to stop here in the next podcast, I will go into more detail. In the next cardio from a collagey podcast, I'll go into more detail and finish basically finish up the entire risk mix. So I wish all the best. If you have any questions, feel free to reach out. I also offer one on one tutoring for the USML is step one, two and three for shelf exams. Those are areas I focus on. Although I can also tutor to med school exams. So feel free to reach out. If you ever needed that, the email is Divine Intervention Podcasts at gmail.com. And I wish all the best. Have a great rest of the weekend. God bless. Thank you.

Automaticity (the ability to depolarize spontaneously).

Ivabradine.

Any agent that blocks the AV node (e.g., beta-blockers, non-dihydropyridine CC Bs), as this increases conduction through the accessory pathway.

Blocking Na+ channels widens the QRS complex (ventricular depolarization). Blocking K+ channels prolongs the QT interval (ventricular repolarization).

Quinidine.

Use dependence (or use-dependence).

Funny current ($I_f$), L-type Calcium influx, and Potassium efflux.

By blocking sodium channels specifically during Phase 2 (the window current).

Class 1 C agents, because they unbind very slowly from the sodium channel.

Synchianism (and it is a muscarinic receptor antagonist).

Ivabradine.

Resting state (Phase 4), Open/Activated state (Phase 0), and Closed/Inactivated state (Phases 1-3).

Funny current ($I_f$), L-type Calcium influx, and Potassium efflux.

By blocking sodium channels specifically during Phase 2 (the window current).

Class 1 C agents, because they unbind very slowly from the sodium channel.

Synchianism (and it is a muscarinic receptor antagonist).

Ivabradine.

Resting state (Phase 4), Open/Activated state (Phase 0), and Closed/Inactivated state (Phases 1-3).