in this lecture I'm going to talk about
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 将细胞去极化至约10毫伏正电压，这称为0相
finally the L-type calcium channels 最后是L型钙通道
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 快速复极化称为阶段3，由逐渐引起
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 然而，它具有很长的不应期，意味着它会恢复
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 通过快速阻断适度抑制0期去极化的药物
sodium channels they also prolong repolarization by blocking 钠通道它们也通过阻断延长复极化
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 心律失常本身因此权衡风险与利益之前是非常重要的
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 室上性和室性快速性心律失常以及心房颤动
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 β受体不幸的是，胺碘酮也与许多不良有关
effects such as pulmonary fibrosis blue-grey skin discoloration neuropathy 影响如肺纤维化的蓝灰色皮肤变色神经病变
hepatotoxicity corneal microdeposits and because it contains iodine 肝毒性角膜微沉积物，因为它含有碘
Amiodarone also can cause thyroid dysfunction 胺碘酮也会引起甲状腺功能紊乱
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 现在让我们继续研究4类抗心律失常药物，以便4级药物起作用
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 通道阻滞剂不像二氢吡啶类，主要作用于二氢吡啶类
periphery causing vasodilation nondihydropyridines are much more selective 引起血管舒张的外周非二氢吡啶更具选择性
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 钠钙交换器可以在两个方向携带钠和钙，所以现在是什么
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 有效治疗尖端扭转型室性心动过速和地高辛诱导
arrhythmias and with that I wanted to thank you for watching I hope you
enjoyed this lecture and as always stay tuned for more