Pharmacology - ANTIARRHYTHMIC DRUGS (MADE EASY)

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