Class IV antiarrhythmics: Calcium channel blockers and others

Chapters:

Watch video only

Introduction0:00–0:32

Antiarrhythmic medications help control arrhythmias or abnormal heartbeats. There are four main groups of antiarrhythmic medications.
Class one sodium channel blockers, class two beta blockers, class three potassium channel blockers, class four calcium channel blockers and miscellaneous antiarrhythmics or unclassified antiarrhythmics.
Now, we'll focus on class four and miscellaneous antiarrhythmics in this video. First, let's start with two main types of cells within the heart pacemaker cells and non pacemaker cells.

Pathophysiology0:32–4:45

Pacemaker cells build the electrical conduction system of the heart, which consists of the sinoatrial node or sa node, the atrial ventricular node or a V node, the bundle of his and the purkinje fibers.
Pacemaker cells have a special property called automaticity, which is the ability to spontaneously depolarize and fire action potentials.
On the other hand, non pacemaker cells also known as cardiomyocytes make up the atria and ventricles and they give the heart its ability to contract and pump blood throughout the body.
Now, in contrast to non pacemaker cells whose action potential has five phases, 0123 and four and action potential in pacemaker cells has only three phases, 40 and three heres, a graph of the membrane potential versus time for a pacemaker cell phase four, also known as the pacemaker potential starts with the opening of the pacemaker channels.
The current through these channels is called pacemaker current or funny current if and it mainly consists of sodium ions.
These sodium ions cause the membrane potential to begin to spontaneously depolarize. And as the membrane potential depolarizes voltage dependent T type calcium channels open up, thereby further depolarizing the pacemaker cell.
As calcium enters the cell, voltage dependent L type calcium channels open up, causing more calcium to rush into the cell.
Ultimately depolarizing the membrane to its threshold potential. This marks the start of phase zero, which is also known as the depolarization phase.
Now, phase zero in a pacemaker cell is caused by an influx of calcium ions through the voltage dependent L type calcium channels that started opening at the end of phase four.
But compared to phase zero of a non pacemaker cell, which consists of a rapid influx of sodium ions. This influx of calcium ions isn't that rapid.
So the slope of phase zero in a pacemaker cell is more gradual. Also during phase zero, the pacemaker channels and voltage dependent T type calcium channels close.
Finally, during phase three, which is the repolarization phase, L type calcium channels close and potassium channels open up resulting in a net outward positive current at the end of repolarization pacemaker channels open up and we start over with phase four again during phase four.
There's also an outward movement of potassium ions as the potassium channels responsible for the repolarization phase continue to close.
Finally, it's important to note that besides pacemaker cells, l type calcium channels are also found in non pacemaker cells and they're responsible for phase two or the plateau phase of their action potential.
Furthermore, calcium that passes through these channels along with calcium that's released from the sarcoplasmic reticulum are essential for the contraction of the cardiac myocytes that make up the rest of the heart.
Now, the automaticity of the heartbeat is led by the pacemaker cells that had the fastest phase four, which are normally the pacemaker cells found in the SA node.
The sa node virus, an electrical signal that propagates throughout both atria, making them contract. The signal gets delayed a bit as it goes through the A V node, then goes through the bundle of his to the purkinje fibers of both ventricles, making them contract as well.
When the electrical signal of the heart doesn't follow this path, it's called an irregular heartbeat or arrhythmia. For example, let's say a part of ventricle begins to fire off action potentials at a rate that's even faster than the SA node.
This area of the heart essentially flips rolls with the sa node firing so fast that the pacemaker cells in the SA node don't get a chance to fire at that point.
The heartbeat is being driven by the ventricles. All right, switching gears and moving on to pharmacology.

Mechanism of Action4:45–5:32

Calcium channel blockers bind and inhibit voltage dependent l type calcium channels. And they're subdivided into two main groups.
Dihydropyridines and non dihydropyridines. Dihydropyridines like amLODIPine, niCARdipine and Nifedipine are highly selective for calcium channels on the vascular smooth muscle tissue.
So, they're primarily used to treat hypertension. On the other hand, non dihydropyridines are the class for antiarrhythmics and they include verapamil and dilTIAZem.
These medications work by targeting the pacemaker cells and non pacemaker cells in the heart. In pacemaker cells, they decrease the amount of calcium entering the cell during phase four and zero, causing a slower pacemaker potential and slower depolarization.

Class IV Antiarrhythmics5:32–6:46

Moreover, by prolonging phase four and zero. Class four, antiarrhythmics also prolong the effective refractory period or E RP, which is the period of time that the cell is unexcitable to new stimulus.
This way, they reduce the firing of the sa node, eventually decreasing the heart rate. But besides decreasing the activity of the essay node, they also decrease conduction velocity through the AV node on the ECG.
This shows up as a longer pr interval which is the time between the onset of atrial depolarization and the onset of ventricular depolarization.
On the other hand, in non pacemaker cells like cardiac myocytes class four antiarrhythmics decrease the amount of calcium entering the cell.
This way, they decrease the amount of calcium available inside the cell, weakening the force generated during heart contraction.

Indications6:46–7:42

Now, verapamil is highly selective for cardiac calcium channels. Thus, it's primarily used to treat angina pectoris and nodal arrhythmias such as supraventricular tachycardia, supraventricular tachycardia is a type of arrhythmia caused by an impulse that originates above the heart's ventricles.
And there are a few different types, paroxysmal supraventricular tachycardia, atrial fibrillation and atrial flutter on the flip side.
DilTIAZem blocks both cardiac and vascular calcium channels. So it can be used to treat hypertension in addition to supraventricular tachycardia.
But even though it's less cardioselective than verapamil dilTIAZem is still more cardioselective than the dihydropyridine calcium channel blockers, which is why it's considered an antiarrhythmic medication.

Side Effects7:42–8:34

Common side effects of class four antiarrhythmics include constipation, flushing and hyperprolactinemia. But the most dangerous side effects include heart block and sa node depression, which can lead to heart failure as far as drug interactions go.
Class four antiarrhythmics should be avoided in individuals treated with beta blockers because beta blockers also depress conduction velocity through the v.
Ultimately, this can result in AV block which is a partial or complete disruption of electrical impulse conduction from the atria to the ventricles.
Finally, the antidote for class four overdose includes beta one adrenergic agonists or other medications that increase the influx of calcium ions.
All right. Now, moving on to miscellaneous antiarrhythmics like adenosine, digoxin and magnesium adenosine is administered intravenously and it has a rapid onset of action of 20 to 30 seconds and duration of action of only 10 seconds.

Adenosine8:34–9:56

Now, adenosine works by stimulating adenosine receptor subtype one or a one which are on pacemaker cells. This indirectly opens potassium channels.
But at the same time inhibits L type calcium channels. Moreover, by opening potassium channels, adenosine hyper polarizes the cell and inhibits the pacemaker current, eventually decreasing spontaneous firing of the sa node and lowering the heart rate.
On the other hand, by inhibiting L type calcium channels, adenosine decreases the amount of calcium entering the cell, thereby preventing depolarization and decreasing conduction velocity through the AV node.
These properties make adenosine useful in the treatment and diagnosis of paroxysmal supraventricular tachycardias. It should be used with caution though as if there is an accessory pathway such as in wolf Parkinson white syndrome.
Adenosine can lead to severe arrhythmias like ventricular fibrillation. Common side effects include flushing hypotension, bronchoconstriction, dyspnea and chest pain.
Next step is digoxin which mimics the effect of the vagal nerve, thereby decreasing the heart rate and reducing conduction velocity through the AV node.

Digoxin9:56–10:22

However, digoxin has a narrow therapeutic window and an overdose could paradoxically cause arrhythmias. The most important one is atrial tachycardia with block which is very specific to digoxin toxicity.
Finally, magnesium, more specifically magnesium sulfate and magnesium chloride. Their mechanisms are unclear but what is clear is that they are very effective in the treatment of severe arrhythmias and especially torsades, the point, which means the twisting of points because the QR S complexes seem to twist around the isoelectric line as an additional benefit.

Magnesium10:22–10:51

It can be used to reverse the arrhythmias caused by digoxin. Now, we wanna make a simple and fun mnemonic that'll help you efficiently memorize and retain all these pharmacology facts.

Memory Palace10:51–13:47

So we're taking a road trip to see all the antiarrhythmic medications. The first stop was at the C for the sodium channel blockers.
The second stop was at a blocked section of road for the class two antiarrhythmics or beta blockers. The third stop was at a banana farm for the potassium channel blocking class three antiarrhythmics.
And finally, we'll go to a dairy farm for the class four antiarrhythmics which block calcium channels. So on this farm, there are four large milk bottles to represent class four antiarrhythmics for verapamil.
Let's use a wrapping vampire and he's running this farm to keep the cows happy. We have a bunny with a heart shaped spot who's playing the drums off beat to represent arrhythmias.
Now milk is not selling well these days. So the vampire also built an oil drill for dilTIAZem.
Let's wrap a BP cuff around it to help you remember that? Unlike Verapamil, this drug can be used to treat hypertension for the side effects of class four antiarrhythmics.
Lets put an outhouse on the farm to represent constipation hanging on the side of the outhouse. We have a heart shaped shield to represent heart block inside.
There's a frozen heart on the toilet which represents bradycardia and finally let's have a cow licking the frozen heart for hyperprolactinemia.
Now, beyond the farm, there's an unexplored forest where we'll put the unclassified antiarrhythmics Aladdin who represents adenosine is living in these woods and he's trying to get a job at the farm.
So he's wearing a necktie that's too tight, which represents bronchoconstriction. One of the main side effects, it's making him dizzy, representing hypotension and his face is red to help you remember flushing?
Now, one of the ox escaped from the farm and it also living in the woods. He's digging a hole since he represents Digoxin.
And he's burying a window. He broke during the breakout to represent its narrow therapeutic window.
He's also burying a poor drummer bunny who's carrying a heart shaped shield since it witnessed his escape, this will help you remember that Digoxin can lead to arrhythmias and heart block.
Finally, for magnesium, let's use a hiker with a giant magnet who's walking in the woods. He's carrying a rhythmic gymnastic ribbon that resembles the ECG pattern seen in torsades de pointe.
Since it's especially effective in treating this type of arrhythmia. Since it's also used to treat digoxin toxicity.
Maybe he'll walk by the scene of the crime and discover the buried shield with his magnet. All right, as a quick recap class four antiarrhythmics also known as calcium channel blockers inhibit L type calcium channels in both pacemaker cells and non pacemaker cells in pacemaker cells.

Review13:47–15:16

They decrease the amount of calcium entering the cell during phase four and zero, causing a slower pacemaker potential and slower depolarization, thereby prolonging the effective refractory period.
This way, they reduce firing of the sa node and decrease the heart rate. While at the same time, they decrease conduction velocity through the AV node on the ECG.
This shows up as a longer pr interval. Class four.
Antiarrhythmics include verapamil and dilTIAZem. And they're primarily used to treat supraventricular tachycardias such as paroxysmal supraventricular tachycardia, atrial flutter and atrial fibrillation.
On the other hand, miscellaneous antiarrhythmics include adenosine, digoxin and magnesium. Adenosine increases potassium efflux and inhibits calcium influx to hyperpolarize the cell and slow down the heart rate.
Digoxin increases parasympathetic activity to slow down the heart. But it has a narrow therapeutic window and could cause atrial tachycardia with AV block.
This could be reversed by magnesium, which also works well for treating torsades de point. But wait, there is more.
Here's a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map15:16–15:25

Stay tuned for the answers after the credits.