Parkinson drug

- [voiceover] heyyoutube, this is dr. joel. in this video, i'm gonna be covering the antiarrhythmic agents. i'm gonna start with areview of cardiac physiology, and then jump right intothe agents themselves. i'll cover the class i, class ii, class iii, class iv, class v, and then just give yousome departing thoughts and then i will finishoff with a couple of

knowledge challenge questions, just to see where you're at. ok? let's get started. in order to do a really good review of the cardiac antiarrhythmic agents, it's first important important for me to cover a little bit of cardiac physiology, starting first with thecardiac action potential. and that's because this action potential

is a little bit differentthan the action potential that you're going to see in nerves. also, a solid understandingof this action potential will help you later understand why the drugs work the way they do. so, this picture on the right represents a cardiac action potential. and, one thing that youneed to understand is that this action potential is going to be

a little bit different depending on which part of the heart you're measuring. however, the principlesthat i'm about to cover will apply to all of thosetissues in the heart. and, if you want to, youcan click on this link, which will take you to a picture that i think does a really cool job about showing the differences in the cardiac action potential

in the different sections of the heart and that also how all thoseelectrical depolarizations add up to make theelectrocardiogram wave form. anyway, on the x axis, we have time and on the y axis, we have voltage. in the polarized state, the heart rests at about negative 95 millivolts. an action potential cycletakes about 200 milliseconds. and that number changes depending on

which part of the heart you're in or which tissue you're sampling. so, on this graph, you can see that the heart starts atabout negative 95 millivolts then it very quickly shootsup to about 20 or so, by this graph, pause at 20 millivolts. it stays there for a bit, and then the cell startsto repolarize itself. and that's the cycle.

i'm going to add a cell membraneat the top of this picture and i'm going to walk through the phases of the action potential one at a time and what i want you to do is, i want you to imagine thatabove this cell membrane is the extracellular space and below this membrane isthe intracellular space. ok, starting off with phase 0, which is the depolarization phase.

this is caused by a opening of voltage-gated sodium channels. and these are very fast,rapid-acting channels that allow a large amount ofsodium to move very quickly. sodium is positively charged, so if positive things come into the cell, then the cell becomes more positive. ok, does that make sense? basically, that's why you seethis huge skyrocketing here

of the voltage fromnegative 95 to positive 20. it's because those positive sodium ions are moving in very quickly. next is phase 1, which is the initial repolarization phase, which is basically causedby the rapid inactivation of those sodium channels. almost as quickly as they open,they start to close again. at the same time, voltage-gatedpotassium channels

start to open allowing potassium to efflux or exit the cell. potassium is also positively charged. so if you have positivethings leaving the cell, then the cell becomesmore negative, right? and that's why there's a littledip there in the voltage. next, with phase 2, you get calcium channelsand they begin to open. calcium, again, also positive.

positive things coming into the cell would make the cell more positive. but potassium is still moving out, so that would make the cell more negative, and hence you get this plateau phase. it kind of balances out for a little bit. it's not exactly flat, but it's close. we still call it the plateau phase. and, as you know, thecalcium plays an effect

on how the muscle cells contract. so that's important aswell for contraction. next is the rapid repolarizationphase, which is phase 3. more of the voltage-gatedslow potassium channels are opening and they allowmore potassium to rush out and the calcium channels begin to close so the cell starts to move back down to a negative value, a strong negative value. and you have to remember,

the sodium-potassium atpase pump is also chugging along this whole time. it's still working, it's still pumping potassium in and sodium out, which is just another factor that is driving that cell backdown to its polarized state. lastly is the fourth phase, which is the resting potential phase. basically, the cell's at rest.

it's waiting for the nextaction potential to hit and that leads us back around to phase 0. so, three very important ions for the cardiac action potential. each of these ions plays an important part in how the electricity,the action potential or the wave of depolarization, moves through the heart, how quickly it moves, how fast it reacts,

how quickly it resets itself. and we're going to talk about drugs that affect sodium channels, potassium channels and calcium channels. so, you can see whyunderstanding the physiology helps the drugs to make more sense. awesome. let's move on. the next important physiology topic are the voltage-gated sodium channels.

there are important for us to understand because various drugs will affect this sodium channel when it's in different states. ok, so we need to understand it. a couple of unique properties of the voltage-gated sodium channels. first of all, it is voltage-gated. that means that it opens and closes

in response to differentmembrane voltage potentials. not necessarily to a receptoror a chemical change, but to a voltage change. the next important thing are these states. the first state is the deactivated state, the second is the activated, and the third is the inactivated. and right away, you might be wondering, deactivated sounds a lot like inactivated.

that's kind of strange. and it's true. conversationally, we do use those words kind of interchangeably. but they do mean different things when we're talking aboutthese sodium channels. so, let's start with the firststate, the deactivated state. in the deactivated state, the... and you have to keep thesestraight in your head...

the activation gate is closed, and that's depicted here by the narrowing in the channel itself. however, the inactivation gate is open. the inactivation gate work differently than the activation gate. the inactivation gate is kindof like a plug on a string, or a plug that you might use in a bathtub. so, in the deactivated state,

the activation gate is closed and the inactivation gate is open. the channel, as a whole, is closed and if we look down atour graph at the bottom, this represents phase 4 inthe cardiac action potential. it's in a resting state, it's waiting. there are a lot of sodium ionsthat are waiting to influx and to cause that rapid depolarization. in the activated state,

which corresponds to phase 0 in the cardiac action potential, the activation gates open and there's a largeinflux, a very fast influx of sodium into the cell, which causes the depolarization. once the maximum voltage is reached, we get to our next state,which is the inactivated state, where the inactivation gate closes.

something like this. again, sodium ions cannot get through because the gate as a whole is closed. and that little pendulumgate at the bottom, which is the inactivation gate, cannot be reopened untilthe membrane repolarizes. so, as you can see from our graph below, this represents phases 1, 2 and 3 and this also represents theeffective refractory period.

because that little gate will not reopen until the cell is repolarized and the voltage-gated channelas a whole resets itself, no amount of electrical stimulation will cause another action potential. i mean, that's the basic definition of what an effective refractory period is. then, once the cell repolarizes, once we get back to phase 4,

the voltage-gated sodiumchannel resets itself back to the deactivated state wherein the activation gate is closed and now we're ready foranother action potential and another surge ofsodium ions into the cell. and now for a few words on refractory periods and arrhythmias. the picture on the rightrepresents a purkinje fiber branch where it branches intomore than one pathway.

in this example, theaction potential starts at the top of the picture and moves down. so, what does this littlehollow area represent? it could be anything really. it could be a blood vessel. it could be previous scar tissue. it could be just a normal branch point in the purkinje fiberor many other things. so what happens is thatthe action potential starts

at the top of the heart andbegins to move very quickly down through the purkinje fibers. and i want you to imaginethe head of the arrow as the leading edge or theleading wave of depolarization and the tail of the arrow representing the refractory period, or that tissue that cannot be restimulated because it's still resetting itself. it's refractory.

so the action potentialcontinues to move down until we get to this point. what happens where these two waves of theaction potential meet? well, nothing really becauseboth sides are refractory, so one action potential hitsthe other action potential and neither one of thetwo can go any further because the tissue behindboth is refractory. well, that works fine innormal cardiac tissue,

but what if we have an area of ischemia or an area of damage, an area that causes essentially a one-way directional tissue? so, this example now on the right has a little area of ischemia, or damage, and that tissue will onlyallow an action potential to move through it in one direction. so again, the actionpotential starts at the top

and it moves down through the tissue. you can see that theaction potential is stopped at this one-way point on the left branch of the purkinje fibers, but on the right branch of thepurkinje fibers it continues. now look at this. at this point, the actionpotential has reached the other side of the one-wayelectrical valve, if you will. and so the action potentialcan go through that tissue.

it might go through a little bit slower, but it can penetrate in this direction. uh-oh. you see the problem here? by the time the action potential gets through the ischemic tissue, it has reached purkinjefibers that are in phase 4, purkinje fibers thatare ready to fire again. and what you get is a loop.

it continues to fire and fire and fire and fire very rapidly. this can cause a tachy-arrhythmia. does that make sense? so, now, what if we take this same example of the ischemic tissuein the purkinje fibers but we change the refractoryperiod by adding a drug. well, the same thinghappens to begin with. the action potential begins,

comes down through the purkinje fibers. you can see now, however, that the refractory period is longer. the previous tissuestill is not yet reset. it's still refractory. and the action potential continues down. it splits at the next branch point until it hits that point whereit can try to come back up through the one-way ischemic tissue.

however, you can see thetissue on the other side is not yet past its refractory period, so it cannot continue inthat loop that we saw before. we have essentially squashedor killed the arrhythmia by lengthening the refractory period. so now that we've discussedthe refractory periods and arrhythmias, is it alittle bit easier to see how, if drugs change the action potential and the refractory period,

then we can change oreven improve arrhythmias? and that's what we're gonnastart talking about next, starting first with theclass i antiarrhythmics, which are sodium channel blockers. now let's talk about the class ia agents. i'm using a slightly different picture now to represent the graphof the action potential, but the concepts are all the same. and this picture, in black,

represents a standardcardiac action potential that has no drug effect. the class ia agents change the shape of the action potential to something like this. they work by blocking sodium channels. remember those fast-acting sodium channels that cause a very fastdepolarization at phase 0? well, you can imagine that

if those were blocked slightlyor inhibited slightly, it would decrease the rate and the rise of this action potential. also, even though we'retalking about class i agents, which are sodium channel blockers, class ia agents have a little bit of potassium channel action, and that prolongs phase 2 because it decreases the speedthat the cell can repolarize

and this extends the durationof the action potential or increases the effectiverefractory period. class 1a agents are typicallyused for things like ventricular tachy-arrhythmias, paroxysmal recurrent atrial fibrillation, and wolff-parkinson-white syndrome, for which you would use procainamide. and lastly, the three most common examples of the class ia agents are

disopyramide, quinidine and procainamide. alright, now the class ib agents. the class ib agents actually cause a little bit of the shorteningof the action potential, and so they change the shape of the curve to look something like this. their mechanism of action is of course relatedto the sodium channels because we're still talkingabout class i agents.

however, they don't block phase 0 as much as the class ia agents. also, they have no effecton the potassium channels but instead decrease the residual sodium plateau influx, which essentially helpsthe cell to repolarize and decreases the lengthof phase 2 on our curve. class ib antiarrhythmics are used for ventricular arrhythmiasor tachy-arrhythmias.

they have no use foratrial tachy-arrhythmias. the three most common examples of the class ib antiarrhythmics are mexiletine, lidocaine and phenytoin. the class ic antiarrhythmic agents have the largest effect on phase 0 without a significant shiftof the action potential. their mechanism of action is related to a strong block of the sodium channels,

which again causes this large decrease of the rate and rise ofthe action potential. they are used for paroxysmalatrial fibrillation and the best threeexamples for this class, flecainide, moricizine and propafenone. so, right about now,you're probably thinking, how in the heck am i goingto remember all that? well, there's a couplethings that might help you. so, first of all, whenyou're thinking about

the graph of the actionpotential of each of these sub-classes of thesodium channel blockers, i wouldn't organize it inmy brain as ia, ib and ic. i would actually remember it as b, a, c, and that's just because that's the order that the graphs descend away from the normal cardiac action potential. next, for remembering all the drug names, there's a pretty cool mnemonic

that pretty much everybody uses, and that is, what i like for lunch a double quarter pounder. so, the class ia, dqp,double quarter pounder, what do you want on it? mayo, lettuce and pickles, mexiletine, lidocaine and phenytoin. and more fries please, moricizine, flecainide and propafenone.

alright? i hope that helps. ok, now to cover theclass ii antiarrhythmics. these are also known as beta blockers, and beta blockade in the heart is mostly talking about beta 1 blockade because beta 1 isdefinitely very important to the way that the heart senses an increase in sympathetic tone. so, essentially, byblocking beta 1 receptors,

we are decreasing thesympathetic tone to the heart. this decreases the conductionspeed through the av node. also, this would decrease the automaticity of irritable cardiac tissue. so, really quick, let'sshow what's happening. the red dot is the sa node. the green dot is the av node. the sa node fires, which sends an electrical signal

through the atrium to the av node. the av node slows thatelectrical impulse down just a little bit to givethe atria time to contract and give the ventricles a pre-load kick. then, that same electrical impulse finally gets through the av node and it's passed onthrough the bundle of his and the purkinje fibers to the ventricles, so that they can contract.

well, what would happen if that right atrium was very irritable. what if there were a lotof ectopic pacemakers firing off in an uncoordinatedand unrhythmic manner. and furthermore, what if that av node had a very short refractory period, kind of like what happens normally when that tissue is stimulated by sympathetic nervous system.

well, the av node would try to transmit as many of those atrialdepolarization waves as it could, which would result in a tachyarrhythmia. beta blockers would acthere, at the av node, to decrease the conduction or increase the effectiverefractory period. also, beta blockade would decrease the number of ectopic pacemakers. so, let's subtract a few of those.

so, now, this is what we're looking at. ok? so, that leads us right into our uses. beta blockers are great fordecreasing tachyarrhythmias and especially supraventriculartachyarrhythmias. also, beta blockers havebeen clinically proven to decrease the mortality after an mi. as for examples, here's a very short list of some beta blockers

and a good way to remember beta blockers is that they usually end in o-l-o-l. however, look at carvedilol. carvedilol does not end in o-l-o-l. it ends in i-l-o-l. it's a little bit differentand has some unique properties. do you remember what thoseunique properties are? well, in addition to being anon-selective beta blocker, carvedilol also blocksthe alpha 1 receptor.

class iii antiarrhythmics. these are the potassium channel blockers, and because they blockthe potassium channel, they increase the durationof the action potential, thus causing an elongation of the effective refractory period, as we've previously discussed. comparing class iii agents, or these potassium channel blockers,

to the class i agents, which are the sodium channel blockers, it has been shown thatthere is less of an effect with the class iiiagents on ischemic tissue than with class i agents. class iii antiarrhythmics areused for syndromes such as wolff-parkinson-white syndrome, ventricular tachycardias, and atrial tachycardiasor tachyarrhythmias.

some examples include amiodarone, bretylium, dronedarone, ibutilide, and sotalol. a few important things topoint out amongst those drugs are amiodarone and sotalol have additional antiarrhythmic properties than just potassium channel blocking. so amiodarone, for example,is a great antiarrhythmic. it's used very often.

it's used in acls protocol. it has class i, ii, iii and iv activity. it's a good drug. you need to know that drug. high yield, high highyield for your tests. sotalol, in addition to beinga potassium channel blocker, also has beta-blocking activity, and you can remember thatbecause it ends in a-l-o-l, which is close to theo-l-o-l of beta blockers.

and lastly, how do you rememberthat short list of drugs? most people remember it by thinking, a big dog is scary. ok, now on to the classiv antiarrhythmics, which are the calcium channel blockers. the mechanism of action for the antiarrhythmic properties of calcium channel blockers are that they blockl-type calcium channels,

which decrease the conduction through the av node and also increase theeffective refractory period of the av node. and we've talked alreadyabout how those two mechanisms cause an abatement, or adecrease, in the arrhythmia. another cool thing about thecalcium channel blockers, if you think about it, is that this mechanism of action

sounds a lot like themechanism of the beta blockers, or the class ii drugs. and that's kind of true, however, the nice thing about using the calcium channelblockers versus the beta blockers is that we free up or don't bog down the adrenergic system. thus, we can get the effect that we want without necessarily having to block

the heart's ability to respondto adrenergic stimulation. uses for these calciumchannel blockers are, first, to prevent the recurrence of paroxysmal supraventricular tachycardias, not to stop an acute tachycardia, but to prevent a recurrence. so, they're used more forlong-term maintenance. also, they reduce ventricular rate in patients with atrial fibrillation.

the two examples of thecalcium channel blockers that are used for theirantiarrhythmic properties are both non-dihydropyridinecalcium channel blockers, verapamil and diltiazem. and both of those are very commonly used so they are high-yield. so try to keep those in mind. alright, let's move on. now to the class v antiarrhythmics.

these are a group of unrelated drugs that all have some kind ofantiarrhythmic property. they don't fit nicely intothe other four categories that were originally definedin this classification system, the vaughan-williamsclassification system. they are useful as antiarrhythmics. we do use them. so, we just made a fifthclass to put them in. and there are several of these drugs.

i'm gonna cover three of them: digoxin, adenosine and magnesium. first up is going to be digoxin, which is a high-yield drug. you really have to know this drug. so, i'm gonna go intoa little bit of detail on the mechanism of action. alright, so, here'sthe cell membrane again with the extracellular space on top

and the intracellular space on the bottom. digoxin works by inhibiting the sodium-potassium atpase, or the sodium-potassium pump. and we know that thispump works by using atp to push out three ions of sodium for every two ions ofpotassium that it brings in. normally that would mean that the extracellular concentrationof sodium would increase

while the intracellularconcentration would decrease. the cell can then usethat higher concentration, or that gradient of sodium,on the extracellular side to provide energy todo other kinds of work. and, one of those other kinds of work is to power the sodium-calcium exchanger, which is a membraneprotein that the cell uses to get calcium back out of the cell. and it does that by exchanging

three ions of sodium, each onewith a positive one charge, for one ion of calcium, whichhas a positive two charge. ok, so does that make sense? that's what's supposed to happen without any inhibition or drugs. digoxin, like i said, inhibitsthat sodium-potassium atpase, or that pump, which meanssodium isn't pumped out as well or as efficiently,which in turn means that calcium is not pumpedout as well or as efficiently.

so, you get an increased intracellular concentration of calcium. and i've mentioned already that calcium is one of the important ionsin the cardiac action potential and in maintaining therhythm of the heart. i also mentioned that calcium plays a part in how the muscles contract, or in this case, theheart muscle contracts. so, digoxin plays a big part

in changing the inotropy of the heart, but it also changes refractory periods. so, when digoxin is usedas an antiarrhythmic, it's mostly used in cases of afib or a flutter with rapid ventricular response. we also sometimes use digoxinfor heart failure patients taking advantage of theanatrophic effects. ok? the second class v antiarrhythmic on my list is adenosine.

adenosine is a pretty cool drug if you've ever seen it work in the clinic. it works on adenosine receptors, and these are g-protein-coupled receptors, which i've highlighted in red because that's an important topic and, if you're not veryfamiliar with those, you should brush up on those if you're preparing for your board exams.

the ultimate effect is goingto be cell hyperpolarization leading to a transient, very short-term heart block in the av node. and, like i said, it'spretty cool to watch because the patients feel it. their heart stops fora brief second or two and in all the casesthat i've seen at least, the heart starts back up again, but then it starts back up again

in a normal sinus rhythminstead of a tachyarrhythmia. because of its affect on the av node, adenosine is used forsupraventricular tachycardias or tachyarrhythmias. so, that would be likeav reentrant tachycardia or av nodal reentrant tachycardia. and then, on to our lastclass v antiarrhythmic, which is just magnesium. magnesium is important andhigh-yield for your boards

only for really two things that i can think of that i know of, and that is eclampsia/pre-eclampsia, which you can lump together, and then torsades, whichis another high-yield topic that you should probably look into. it's basically a veryspecific wave form on an ekg that can signify an impending possible cardiac disaster,

which even could leadto sudden cardiac death. it doesn't happen really allthat often in the real world, but it's definitely a board favorite. torsades de pointes isa french word meaning twisting of the points ortwisting of the spikes, and that's just because, youcan see this wave form here looks like it's twistingback and forth like a ribbon. alright, good job for hanging in there through this long lecture.

we've covered the class i, ii, iii, iv and iv antiarrhythmics, and you're probably wondering, dr. joel, can you please give mesomething to help me to remember all these antiarrhythmics? and the answer is, why yes i can. how about you think of it as some block potassium channels. that's for the class i, ii, iii and iv,

for sodium channel blockers, beta-blockers, potassium channel blockers and calcium channel blockers. also, another departing thought, if you really want toimpress your preceptor, you could know a little bit about the cardiac arrhythmiasuppression trial, the cast trial. this was done in thelate '80s to late '90s

and involved about 1500 patients. basically, it was trying toanswer the question as to what to do with a patientafter they have a heart attack. we know that, after a patientsurvives a heart attack, a common cause of them dying later on is from a lethal arrhythmia. and, part of the reason forthat we briefly touched on when we talked about refractory periods, which is why i'm showingthis image to the right.

so it would make sense to tryand quell those arrhythmias to prolong the patient's life. and that used to be donewith class i antiarrhythmics. this study tested thattheory and actually found that those drugs increasedmortality instead of lowering it. hence, nowadays, we generally try to avoid suppressing arrhythmias inpatients who have had an mi with class i drugs. ok? ok, you've made it this far, good job.

knowledge challenge number 1. to which antiarrhythmic classdoes propranolol belong? propanolol is a class ii antiarrhythmic. remember the mnemonic some block potassium channels? so, class i are thesodium channel blockers, class ii are the beta-blockers, class iii are thepotassium channel blockers, and class iv are thecalcium channel blockers.

also remember that mostof the beta-blockers end in o-l-o-l, so propranolol or esmolol or metoprolol. o-l-o-l. ok, good job, let's move on. knowledge challenge number 2. which antiarrhythmic class has the most effect on phase 0

of the cardiac action potential? alright, it's actually class ic. remember how i was overlaying the changes in the cardiac action potentialwith the class i drugs, and i told you, insteadof thinking about it as class a, b and c,it'd probably be better to think about it as class b, a, c, because that's how thecurves kind of move away from the unaffected, normal physiology?

right, so class c has the strongest effect on that initial fast sodium influx. knowledge challenge number 3. on your er rotation, you're called to help with a "code blue." and as the team quicklyassembles and begins acls, your attending physician asks you, yes you, as the medical student, to run the code.

you're of course very nervous, but it's a teaching hospital and you know that the attending and the team are motivated to help you through. after a few minutes offollowing acls protocol, you ask a team member toprepare a syringe of a drug that is usually listed as asa class iii antiarrhythmic but has properties ofall four of the classes. which drug is this?

d, amiodarone. great drug. you gotta know it. high-yield. you are going to use this drug or talk about this drug in your rotations. alright, good job. hey guys, thanks for watching this video. i really had fun making it and i love working with students,

so if you've got anyquestions or comments, shoot me a message and i will do my bestto get back to you, ok? also, give me a like. those likes keep me motivated. make sure you subscribe if you want to keep up todate on all my newest videos, maybe check out some of thelinks if you've got time. if not, hang in there, keep pushing,

good luck in school, i know you can do it.