Hello everyone.
It's Eric from Strong Medicine, and today, by popular request, I'll be discussing antiarrhythmics.
Antiarrhythmics are a huge topic that I'll dividing up into 7 brief videos, with this
one serving as an introduction, 4 will be on the conventional classes of antiarrhythmics,
1 on those drugs which don't fall into a class, and a final video discussing how to select
the appropriate drug for a specific situation as well as some common antiarrhythmic pitfalls.
By the end of the series, you should be able to describe the classification system for
antiarrhythmics, To list common antiarrhythmics, as well as
their mechanisms, indications, and side effects.
To choose an appropriate antiarrhythmic in specific clinical situations.
And to identify arrhythmias that are the likely consequence of a proarrhythmic side effect.
To get the most out of this series, I recommend a very basic familiarity with the cardiac
action potential, basic ECG reading skills, and of course, familiarity with common arrhythmias.
So as I mentioned, this series comes by popular demand, and the reason for that is probably
because antiarrhythmics are hard to learn.
But why is that?
First, there are many drugs.
This series will cover the 21 most important ones.
Second, the physiology of the cardiac action potential is complex.
The pathophysiology of arrhythmias is also complex.
All antiarrhythmics have proarrhythmic side effects.
So each antiarrhythmic is actually matched with twice as many arrhythmias as they seem
to be at first glance: those that they treat, and those that they cause.
And last, the actions of antiarrhythmics are too complex for a perfect classification system.
But hopefully, this series will help you to overcome all of these obstacles.
I'm first going to tackle that last issue.
The classification system.
This is usually called the Vaughan Williams system, not after the famous English composer
Ralph, but actually after Miles, a pharmacologist and incidentally Ralph's first cousin once
removed.
Miles Vaughan Williams developed this system in the 1960s and 70s, as the precise mechanisms
of antiarrhythmics were first being worked out, with invaluable assistance from his doctoral
student Bramah Singh.
Looking over the literature of the time, Vaughan Williams and Singh seemed to have made quite
the team, coauthoring a number of seminal papers in the field.
So, although it's most commonly referred to as the Vaughan-William system, there is a
minority opinion that both scientists should be credited with the eponym the Singh-Vaughan
Williams classification system.
I like inclusivity, and see no downside with recognizing a hard working grad student who
made significant contributions of his own, so this is the name that I use, but, it is
less common.
The system divides antiarrhythmics into 4 classes depending upon their primary mechanism
of action.
So there is class I, which consists of sodium channel blockers.
Class II, are beta receptor antagonists, more commonly known as beta blockers.
Class III are potassium channel blockers.
And Class IV are calcium channel blockers.
Class I was subsequently subdivided into 3 subclasses, Ia, Ib, and Ic, the differences
between which I'll discuss in the next video.
This system has advantages and disadvantages.
The primary advantage is that it's simple.
4 fundamental classes based on 4 distinct mechanisms.
Unfortunately, there are some significant disadvantages.
First, some drugs have actions of more than one class.
Second, some drugs don't fall into a class at all, like adenosine and digoxin.
And third, a drug's indications cannot always be easily deduced from its class.
So for example, some class I drugs are used for atrial fibrillation but not ventricular
tachycardia.
And other class I drugs are used for ventricular tachycardia and not a-fib.
So it's sometimes difficult to predict which drugs should be used for which arrhythmia
from first principles.
But despite these disadvantages, in the 50 years since its proposal, no one has come
up with a better system.
Antiarrhythmics are just plain too complicated.
There is one alternative out there called the Sicilian Gambit system, yes, as in the
chess opening.
The Sicilian Gambit tries to address the disadvantages of Singh-Vaughan Williams, but in the process,
sacrifices the simplicity.
So, instead of 4 classes for 4 mechanisms, you have this instead.
More interesting, yes.
More reflective of physiology, yes.
Easier to teach or to use in practice.
No.
So this series will stick with Singh-Vaughan Williams.
At the beginning of the video, I suggested that viewers should have some familiarity
with the cardiac action potential, but before going more into the drugs, let me go through
a 5 minute review of this, because even though you may have studied it before, it's very
easy to forget, and this series will be more challenging if that's the case.
An action potential is a brief alteration in the electrical potential, also known as
voltage, across a cell membrane that propagates along the cell, and spreads from one cell
to the next as a means of sending a signal.
For example when your hand on a stove sends a signal via neurons up to your brain that
this is hot, and your brain sends a signal back down to your hand telling it to move.
Those are action potentials that transmit those messages along the nerves.
There is a similar process that happens in the heart.
In normal situations, a signal is generated by the sinus node, travels via action potentials
through the atria telling them to contract.
The signal then reaches the AV node, where there's a brief delay.
This is then followed by the continuation of the action potential mediated signal through
the His-Purkinje network, eventually reaching the ventricles, and telling them to contract.
Action potentials are generated by a very rapid, carefully regulated, stereotypical
sequence of transmembrane ion channels opening and closing in response to changes in the
surrounding electrical potential.
At different points in time during this sequence, one or another ions are travelling into or
out of the cell based on the electrical and chemical gradients, as well as the varying
conductance of the membrane for those ions.
As conductance changes due to the opening and closing of ion channels, changes in the
transmembrane potential difference comes along very shortly afterwards, which in turn further
alters which channels are open and which are closed.
In the heart, there are two basic types of action potentials.
The first, is called the fast response action potential.
It's called this because it's generated quickly, and thus propagates quickly.
The fast response action potential is seen in typical myocytes in the atria, ventricles,
and the His/Purkinje system.
And this is what it looks like.
It starts at the so-called resting membrane potential, which is negative.
At some point in time, when it receives a signal from a neighboring cell, the voltage
very abruptly increases in what's called phase 0 of the action potential.
This rapid increase in voltage is known as depolarization because the cell membrane potential
goes from being very negative to closer to 0, and actually overshoots to slightly more
positive than 0.
This is followed by a brief decline called phase 1.
Then a relative plateau of voltage called phase 2.
And finally, phase 3 consists of a relatively quick repolarization back to the negative
resting membrane potential, which itself is called phase 4.
There are certain ion currents primarily responsible for each of these phases.
Of specific interest to understanding antiarrhythmics is the inward sodium current that is responsible
for phase 0, and the outward potassium current that is responsible for phase 3.
There are other ion currents going on here, but they are less relevant for antiarrhythmics.
Not totally irrelevant, but less relevant.
The second type of cardiac action potential is predictably called the slow response action
potential.
This is seen in the sinus or SA node, as well as in the AV node.
In the slow action potential, phase 4 is not at an equilibrium, but rather consists of
a gradual depolarization, which eventually hits a specific threshold potential, that
then triggers a phase 0 that is steeper than phase 4, but much less steep than the phase
0 of the fast response action potential.
The slow response action potential has no phase 1 or phase 2.
But there is a phase 3 of repolarization.
One of the primary currents of interest here is an inward current during phase 4 that's
predominantly carried by both sodium and potassium ions.
This current has a number of unusual features, giving it the amusing formal name of the funny
current, often abbreviated I little f.
Phase 0 is driven by an inward calcium current.
As will be relevant when we talk about the calcium channel blockers, there are 2 main
types of calcium channels, T for transient, and L for long-lasting.
It is the L type of calcium channel that is responsible for phase 0.
Last, an outward potassium current is responsible for phase 3.
So at this point, let's predict what the primary effect will be on the action potential from
each of the 4 classes of antiarrhythmics.
Class I are the sodium channel blockers.
Ignoring the funny current, which is not affected by class I antiarrhythmics, sodium channels
play a much more prominent role in the fast response action potential than the slow response.
If sodium channels are relatively blocked in the tissues exhibiting the fast response,
you can imagine that depolarization in those cells will be slowed.
In other words, the upward slope of the action potential will be less steep.
I'm going to skip class II just for a moment.
Class III are potassium channel blockers.
If potassium channels are relatively blocked, phase 3, the repolarization of the cells back
down to a lower membrane potential, will take longer.
This extends the overall duration of the action potential.
Class IV are calcium channel blockers.
The effect of calcium channels most relevant to antiarrhythmics is with the slow response
action potential, where they result in a slowed depolarization.
And to go back to class II, which were the beta blockers, as I'll discuss in the beta
blocker video, their mechanism of action is to antagonize the effect of epinephrine and
norepinephrine, which through the indirect inhibition of normal signal transduction pathways,
results in a subsequent decrease in the calcium current into the cell.
So therefore, the effect of beta blockers on the action potential is very similar to
that of calcium channel blockers.
Now, let's take one final step and ask what the primary effect on the resting EKG would
be from each class, based upon their primary effects on the action potential.
Class I drugs slow depolarization of the fast response action potential, which is seen in
the atria, ventricles, and His/Purkinje system.
On the EKG, the most noticeable effect of this involves the ventricles, specifically,
the widening of the QRS complex.
Remember that the QRS complex represents ventricular depolarization.
Class II and class IV drugs slow depolarization in the slow response action potential, which
is present in the sinus and AV nodes.
Thus, beta blockers and calcium channel blockers slow the sinus rate, and may prolong the PR
interval, which represents physiologic AV nodal delay.
Class III drugs prolong the action potential, and thus, delay repolarization.
On the EKG, the T waves represent ventricular repolarization.
So the consequence of potassium channel blockers is to prolong the QT interval.
That concludes the introduction to this series on antiarrhythmics.
The next video will discuss sodium channel blockers in detail.