in this lecture I’m going to talk about
antiarrhythmic drugs so let’s get right into it as you may already know the
pumping action of the heart is controlled by the heart’s electrical
system the heart contains specialized cells that are able to create their own
electrical impulses and send them to the cardiac muscle causing it to contract
now the cardiac conduction system is made up of five elements number one the
sinoatrial node SA node for short number two the atrioventricular node AV node
for short number three the bundle of His number four the bundle branches and
number five the Purkinje fibers so the normal heart rhythm begins when
electrical signals are sent from the SA node the signal from the SA node causes
the atria to contract pushing blood through the open valves into the
ventricles on the typical electrocardiogram this is represented by
the P wave next electric signal arrives at the AV node and is briefly delayed so
that the contracting atria have enough time to pump all the blood into the
ventricles this is represented by the line between the P and the Q wave at
this point the signal travels to the bundle of His into the bundle branches
this is represented by the Q wave and finally this signal travels through the
Purkinje fibers which causes the ventricles to contract and thus pump
blood from the right ventricle into the lungs and from the left ventricle into
the rest of the body this is represented by the R and S wave the last T wave
represents the recovery of the ventricles
now cardiac cells can be divided into two types first contractile cells which
make up most of the walls of the atria and ventricles and when stimulated they
generate force for contraction of the heart and the second type conducting
cells which initiate the electrical impulse that controls those contractions now
while contractile fibers can’t generate an action potential on their own the
conducting fibers are capable of spontaneously initiating an action
potential by themselves they exhibit so-called automaticity the conducting
cells are primarily concentrated in the tissues of the SA node AV node bundle of
His and Purkinje fibers now normally SA node reaches threshold potential the
fastest which is why it serves as the natural pacemaker of the heart when the
SA node drives the heart rate the cells of AV node bundle of His and Purkinje
fibers do not express automaticity or in other words their spontaneous
depolarization is suppressed however under certain conditions when activity
of the SA node becomes suppressed or the firing rate of these other conducting
tissues becomes faster one of them can become the new pacemaker of the heart
this is why the AV node bundle of His and Purkinje fibers are called latent
pacemakers now before we move on let’s take a closer look at the action
potential of the pacemaker cells versus the heart muscle cells as there are some
important differences between them so in the heart
each cardiac cell contains and is surrounded by electrolyte fluids the
main ions responsible for the electrical activity within the heart are sodium
calcium and potassium when cardiac cells are stimulated by an
electrical impulse their membrane’s permeability change and ions move across
the membrane thus generating an action potential so now the membrane potential
in the pacemaker cells starts at about negative 60 millivolt
when spontaneous flow of sodium mainly through slow sodium channels and opening
of the voltage-gated T-type calcium channels continue slow depolarization
this is referred to as phase 4 once threshold potential of about
negative 40 millivolt is reached the voltage-gated L-type calcium channels
open calcium rushes in and rapidly depolarizes cell to about positive 10 millivolts this is referred to as phase 0 finally the L-type calcium channels close and the voltage-gated potassium
channels open which allows potassium ions to escape thus repolarizing the
cell back to negative 60 millivolts this is referred to as phase 3
after this the cycle just repeats itself also note that there is no phase 1 or
phase 2 in the action potential of the pacemaker cells okay so now let’s take a
look at the action potential of the cardiac muscle cells unlike pacemaker
cells the cardiac muscle cells have resting membrane potential of about
negative 90 millivolts due to the constant outward leak of
potassium through the inward-rectifier channels this resting phase is referred
to as phase 4 now when an action potential is triggered in a neighboring
cell the voltage-gated sodium channels open and sodium rushes in causing a
rapid depolarization to about positive 40 millivolts this is referred to as
phase 0 at this point the sodium channels become inactivated and other
voltage-gated channels begin to open mainly potassium channels which allow
potassium to escape thus bringing about a small dip in membrane potential this
is referred to as phase 1 now something that I didn’t mention is that
during depolarization at phase 0 voltage-gated L-type calcium channels
began to open slowly allowing calcium enter into the cell so now with the
positive potassium ions leaving and the positive calcium ions steadily coming in
we have this electrically balanced ion exchange which keeps the membrane
potential on a plateau this is referred to as phase 2
lastly the plateau phase is followed by a rapid repolarization referred to as phase 3 which is caused by a gradual inactivation of the calcium channels and
continuous outflow of potassium this brings the membrane potential back
to the resting phase 4 so now let’s switch gears and let’s talk about
arrhythmias so what is arrhythmia well arrhythmia is simply a deviation of
heart from a normal rhythm so normal heart rhythm will have a heart rate of
between 60 to 100 beats per minute with each beat generated from the SA node
each cardiac impulse will also propagate through normal conduction pathway with
normal velocity now arrhythmias are generally classified based on heart
rate as bradyarrhythmias when the rate is below 60 beats per minute or
tachyarrhythmias when the rate is above 100 beats per minute however in order to
understand pharmacology of antiarrhythmic drugs we need to focus on mechanisms of
tachyarrhythmias so there are three basic mechanisms responsible for the
initiation of tachyarrhythmias first abnormal automaticity also referred to as
enhanced automaticity this occurs when the cell membrane becomes abnormally
permeable to sodium during phase 4 which results in
increase in the slope of phase 4 depolarization this can cause other
cells to accelerate their automaticity and thus generate impulses faster than the SA
node the second mechanism is called triggered activity triggered activity
involves the abnormal leakage of positive ions into the cardiac cell
leading to this bump on the action potential called afterdepolarization
these afterdepolarizations can occur during phase 2 3 or 4 and if
they have sufficient magnitude they can trigger premature action potentials
now the third mechanism of tachyarrhythmias is called reentry
example of this is wolff-parkinson-white syndrome in which an extra or so-called
accessory pathway exists between the upper and lower chambers of the heart so
normally the electrical signal travels from the SA node to AV node to bundle
branches and once it reaches the Purkinje fibers it stops and waits for
another signal from the SA node now when the accessory pathway appears
the signal travels through this pathway from ventricles back to atria causing
them to contract before SA node fires again this creates this abnormal loop of
electrical activation circulating through a region of heart tissue causing
tachyarrhythmia another example of reentry is atrioventricular nodal
reentry tachycardia AVNRT for short so typically there are two anatomic
pathways for carrying signal through the AV node first pathway is called the fast
pathway because it allows fast conduction however it has a long refractory period meaning it recovers slowly on the other side this second
pathway is called the slow pathway because it only allows slow conduction
and because of that it has short refractory period meaning it recovers
fast so now the signal comes down from the SA node and then it splits and
travels fast through the fast pathway and slow through the slow pathway so the
fast pathway signal reaches the common pathway on the other end well before the
slow pathway signal gets there from there the fast pathway signal spreads to
the ventricles as well as up the slow pathway where it hits the slow signal
causing it to terminate now if a premature beat occurs at the
time when the fast pathway signal is still in the refractory period the
signal will travel down the slow pathway as the slow signal approaches the common
pathway fast pathway comes out of refractory period so now the slow signal
spreads to the ventricles and it also travels up the fast pathway but let’s
not forget that the slow pathway has a short refractory period so by the time
the signal reaches the top the slow pathway is ready to conduct another
signal so what ultimately happens here is that this signal continues to circle
around sending fast impulses which result in tachycardia now let’s move on
to discussing the actual antiarrhythmic drugs so most commonly used
classification of antiarrhythmics is the Vaughan Williams classification which
groups most antiarrhythmics into four classes based on their dominant
mechanism of action now let’s discuss each of these classes so first we have
class 1 drugs which work mainly by blocking sodium channels in the open or
inactivated state inhibition of sodium channels decreases the rate of rise of
phase 0 depolarization and slows conduction velocity class 1 drugs are
subdivided into three subclasses according to their effect on the cardiac
action potential first we have class 1A drugs which moderately depress the phase 0 depolarization by blocking fast sodium channels they also prolong repolarization by blocking some potassium channels so what we’ll
see with class 1A agents is prolonged action potential and prolonged effective
refractory period the agents in this class include Procainamide Quinidine and
Disopyramide these agents are used in the treatment of a wide variety of
arrhythmias such as ventricular tachycardias and
recurrent atrial fibrillation adverse effects include blurred vision headache
and tinnitus which may occur with large doses of Quinidine and some
anticholinergic effects which may occur with the use of Disopyramide secondly
we have class 1B drugs which have relatively weak effect on the phase 0
depolarization due to minimal blockade of fast sodium channels however these
agents shorten repolarization by blocking sodium channels that activate
during late phase 2 of the action potential so what we’ll see with class
1B agents is shorten duration of action potential and shorten effective
refractory period the agents in this class include Lidocaine and Mexiletine
which are mainly used in the treatment of ventricular arrhythmias when it comes
to adverse effects Lidocaine can cause CNS toxicity including seizures while
Mexiletine can cause nausea and vomiting now the third and the last
subtype that we have is class 1C drugs which are powerful fast sodium channel
blockers which depress the phase 0 depolarization markedly they also
inhibit the His-Purkinje conduction system with a limited effect on
repolarization and refractory period the agents in this class include Flecainide
and Propafenone which are mainly used in the treatment of refractory ventricular
arrhythmias when it comes to adverse effects the most common ones include dizziness
blurred vision and nausea also something that I haven’t mentioned yet is that one
of the risk associated with the class 1 agents actually all of them is that
they have potential to actually cause arrhythmias themselves so weighing the risk versus benefit is very important before initiating therapy with these agents now
let’s move on to class 2 antiarrhythmic drugs so agents in this
class act on the beta-1 receptors preventing the action of
catecholamines on the heart so class 2 agents are simply beta blockers beta blockers
depress sinus node automaticity and slow conduction through the AV node which
results in decreased heart rate and decreased contractility examples of beta
blockers commonly used for arrhythmia are Propranolol Metoprolol Atenolol and
Esmolol now Esmolol unlike the other beta blockers is somewhat special in
that it’s given intravenously in an emergency acute arrhythmias and the
reason for that is that it has fast onset of action and very short half-life
which allows it to be titrated rapidly when necessary so the bottom line is
that beta blockers are good choice for treatment of arrhythmias provoked by
increased sympathetic activity and if you want to learn more about them check
out my other videos about adrenergic receptors and beta blockers now let’s
move on to class 3 antiarrhythmic drugs so class 3 agents work mainly
by blocking the potassium channels that are responsible for the Phase 3
repolarization this leads to increase in duration of action potential and
increase in effective refractory period the agents in this class include
Amiodarone Dronedarone Sotalol Dofetilide and Ibutilide there are
mainly used in treatment of supraventricular and ventricular tachyarrhythmias as well as atrial fibrillation and flutter the most widely used
drug in this class is Amiodarone which is very effective for the treatment of
these aforementioned arrhythmias Amiodarone has multiple actions and
besides blocking potassium channels Amiodarone also blocks sodium channels
calcium channels and even some alpha and beta receptors unfortunately Amiodarone is also associated with many adverse effects such as pulmonary fibrosis blue-grey skin discoloration neuropathy hepatotoxicity corneal microdeposits and because it contains iodine Amiodarone also can cause thyroid dysfunction leading to hypo or
hyperthyroidism lastly due to its long half-life Amiodarone can linger in many
tissues for months after discontinuation of therapy now on the other hand we have
Dronedarone which is derivative of Amiodarone it’s less lipophilic and has
shorter half-life it also doesn’t contain iodine so in general it has
better side effect profile unfortunately in many cases Dronedarone doesn’t seem
to be as effective as Amiodarone now Sotalol is a unique drug in this class
because it not only has potassium channel blocking activity but also beta
receptor blocking activity lastly Dofetilide and Ibutilide are
the most selective potassium channel blockers in this class however they’re
also most likely to cause arrhythmias themselves and therefore are typically
initiated in the inpatient setting only now let’s move on to class 4 antiarrhythmic drugs so class 4 agents work by blocking voltage-sensitive calcium
channels during depolarization particularly in the SA and AV nodes
which results in slower conduction in these tissues and reduced contractility
of the heart the agents in this class include Verapamil and Diltiazem which
are the nondihydropyridine calcium channel blockers unlike dihydropyridines which act primarily in the periphery causing vasodilation nondihydropyridines are much more selective for the myocardium and therefore they
show antiarrhythmic actions Verapamil and Diltiazem are most commonly used in
treatment of supraventricular tachycardia and atrial fibrillation and
now before we end this lecture I wanted to briefly discuss some other
antiarrhythmic agents that do not quite fit into any of the classes that we
covered thus far and these are Digoxin Adenosine and Magnesium Sulfate
so let’s talk about Digoxin first and in
order to understand how it works let’s picture a cardiac cell under resting
conditions sodium slowly leaks into the cell and potassium leaks out however
during an action potential additional sodium enters in along with calcium and
additional potassium leaves the cell so at some point we have this imbalance
that has to be restored and this restoration is accomplished by pumps
such as sodium-potassium ATPase which transports sodium ions to the outside of
the cell and potassium to the inside of the cell and we also have sodium-calcium
exchanger which removes calcium from the cell in exchange for sodium and as a
side note here keep in mind that sodium-calcium exchanger can carry sodium and calcium in both directions so now what happens when Digoxin comes around is
that it inhibits sodium-potassium pump by binding to the potassium binding site
this results in the increase in intracellular sodium which then in turn
causes the sodium-calcium exchanger to pump sodium out and bring more calcium
in now this increase in intracellular calcium leads to enhanced myocardial
contractility Digoxin also stimulates parasympathetic system which
increases activity of the vagus nerve this results in the slowing of sinus
node discharge rate and decreased conduction through the AV node these
actions make Digoxin particularly useful for patients with both heart failure and
atrial fibrillation now let’s talk about the second agent which is Adenosine
unlike all the other agents Adenosine is a naturally occurring nucleoside it
works by stimulating A1 type adenosine receptors on the atrium as
well as on the SA node and AV node which results in decreased automaticity
decreased conduction velocity and prolonged refractory period
due to its very short duration of action adenosine has to be administrated by IV
its main indication is an acute supraventricular tachycardia one of the
biggest benefits of Adenosine is that it’s relatively non-toxic with the most
common side effects being chest pain flushing and hypotension now finally
let’s talk about our third agent which is Magnesium Sulfate Magnesium Sulfate
plays an important role in transport of sodium potassium and calcium across the
cell membranes unfortunately its precise mechanism of action for treating
arrhythmias is largely unknown however what we know is that Magnesium Sulfate
administered intravenously is very effective for treatment of torsades de pointes and Digoxin induced arrhythmias and with that I wanted to
thank you for watching I hope you enjoyed this lecture and as always stay
tuned for more


  1. Phenomenal explanation of cardiac action potentials and cardiac drugs! He has an amazing way of explaining things!

  2. Your videos are usually top notch but I find that this one isn't as detailed as it could've been. I'm actually more confused after watching this video than I was coming in, and that's saying something.

  3. 13:49 Na channels in late phase 2?! That can't be right. Can anyone please tell me how Ib drugs shorten repolarisation?

  4. Thank you so much! The video is brief yet quite precise, and the cute clip art for the side effects really aids memory 🙂

  5. Phase 4 of SA node depolarization is by If (funny current) which is a combination of Na/K ions as sodium channels are disabled in SA node


  7. Loved the video ???
    You make pharmacology so much easy to understand especially the side effects cartoons get stuck somewhere in the mind. Always hungry for more videos by you?

  8. You haven't told about the na+ channels which operate during end of phase 2 whilst explaining the graph but you mentioned them during the action of class 1b. So what do these na+ channels at the end of phase 2 do ..Influx or eflux..I'm confused

  9. Amazing videos!!! Really helpful!

    In WPW syndrom does reentry also occur? I thought PR interval is decreased due to accessory pathway.

  10. Thank youuuuuuuu sir from my all heart
    Please keep making these very useful videos ❤️❤️❤️❤️❤️❤️❤️

  11. Please note QT interval represents electromechanical systole. In your talk it is qrs represents ventricular systole. Are you sure about it?

  12. I have a question : when the membran reach – 60 potential after K going out, where are then influxed ca and na going?

  13. Honestly saying , your videos are worth watching. Keep up the good work and thank you for making this topic easy.

  14. Can you please make a Vedio on classification and pharmacology of ANTI ANGINAL DRUGS.. It's needed please make a Vedio on this topic

  15. The heart function is very interesting and the drug side effects are very scary. It's a shame that only as I reach my 40th year and my parts stop working correctly that I take so much more interest in body functions. Even if I only learn how much further evolution needs to go. Lol.

  16. Plz upload drugs about chemotherapeutics
    This is my request
    And thank u sooo much for your videos
    Stay blessed

  17. Thank you! I want to ask that in digoxin mechanism of action u stated that normally Na comes in n K goes out…but normally isn't it 3Na goes out and 2 K comes in through Na K ATPase pump n then digoxin blocks this pump so that more intracellular Na gets accumulated. Plz clarify ?

  18. There are no fast sodium channels in nodal tissue (SA and AV node). Phase 4 and 0 in nodal tissue are due entirely to Calcium influx

  19. This a useless piece of SH!!!!!!!!!!!!T
    You started out with a weak discussion of heart anatomy that we could have done on our own. The part of action potentials is better done in other sights. But when you get to the main points on comparison of the non-nodal and nodal cell action potentials, you just told us what is in simple bio101 text. BIG DEAL! Khan is better.

  20. The lectures which my college professor took a month to explain not even properly u didn't even take half an hour to explain it so clearly

  21. Doesn't digoxin have two pharmacological mechanisms? The first one is the one you explained in the video which is very helpful in Heart Failure because the heart needs contraction however this does not help with arrhythmia. Instead, digoxin has an effect in CNS where it fires the vagus nerve. This increase in vagus nerve inc ACH on the muscarinic receptor and the muscarinic receptor which is on the heart, in turn, slows the heart rate because Muscarinic receptor activates Gi. This activation, in turn, helps with the slowing of the AV node conduction.

    Correct if I'm wrong. Thanks!
    P.S as a P2 pharmacy student I absolutely appreciate your videos

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