Class II antiarrhythmics: Beta blockers

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Introduction0:00–0:32

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

Pathophysiology0:32–5:51

Pacemaker cells build the electrical conduction system of the heart, which consists of the sinoatrial node, or SA node; the atrioventricular node, or AV 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 5 phases, an action potential in pacemaker cells has only 3 phases.
Here’s a graph of the membrane potential vs. time.
Phase 4, 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 0, which is also known as the depolarization phase. Now phase 0 is caused by an influx of calcium ions through the voltage-dependent L-type calcium channels that started opening at the end of phase 4.
But, this influx of calcium ions isn’t that rapid, so the slope of phase 0 is gradual. Also during phase 0, the pacemaker channels and voltage-dependent T-type calcium channels close.
Finally, during phase 3, 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 4 again. During phase 4 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 2 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 have the fastest phase 4, which are normally the pacemaker cells found in the SA node.
The SA node fires an electrical signal that propagates throughout both atria, making them contract. The signal gets delayed a bit as it goes through the AV 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 the 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 roles 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. Now, the autonomic system can also affect cardiovascular function via beta-1 (β1) and beta-2 (β2) adrenergic receptors.
In the heart, the predominant subtype is beta-1; while beta-2 adrenergic receptors are primarily found on smooth muscle cells.
For example, inside blood vessels. Now, in the heart, beta-1 adrenergic receptors are found on both pacemaker cells and non-pacemaker cells.
Once stimulated by norepinephrine or epinephrine, beta adrenergic receptors activate the enzyme adenylyl cyclase, which converts adenosine triphosphate, ATP, into cyclic adenosine monophosphate, cAMP.
Moreover, cAMP is a secondary messenger that activates an enzyme cAMP-dependent protein kinase, PK-A, which phosphorylates L-type calcium channels.
Ultimately, this results in their opening and an increased influx of calcium ions. In pacemaker cells, this influx happens at the end of phase 4; while in non-pacemaker cardiac cells, it happens during phase 2.
Alright, let’s switch gears and move on to pharmacology! Beta blockers bind beta adrenergic receptors in both pacemaker cells and non-pacemaker cells, thereby preventing norepinephrine and epinephrine from binding them.

Mechanism of Action5:51–8:16

Now, beta blockers that mainly target pacemaker cells are actually classified as class II antiarrhythmics and just like all beta blockers, they can be subdivided into selective beta-1 blockers, like atenolol, acebutolol, betaxolol, bisoprolol, esmolol, and metoprolol; or non-selective beta blockers, like timolol and propranolol that target all beta receptors.
Now, here’s a tip: all beta blockers end with the suffix -olol, but only selective beta-1 blockers start with a letter from the first half of the alphabet, A-M; while non-selective beta blockers start with a letter from the second half of the alphabet, N-Z.
Okay, now let’s switch gears and look at the pharmacology of class II antiarrhythmics, in pacemaker cells, they prevent epinephrine and norepinephrine from binding to the beta receptors, which indirectly decreases the number of L-type calcium channels that open.
This decreases the amount of calcium that enters the cell at the end of phase 4. Eventually, this leads to a slower pacemaker potential and on the graph, this is seen as a decrease in the slope during phase 4.
As a result, beta blockers decrease the rate that the SA node fires and therefore, decreases the heart rate. But, besides decreasing the activity of the SA 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, beta blockers also indirectly prevent the opening of L-type calcium channels.
This decreases the amount of intracellular calcium available to the muscle fibers, weakening the force generated during heart contraction.
Ultimately, by reducing the heart rate and contractility, beta blockers reduce cardiac oxygen demand. Now, class II antiarrhythmics are used in the treatment of supraventricular tachycardias, such as atrial fibrillation and atrial flutter.

Indications8:16–8:37

Interestingly enough, they are also used as a part of therapy and prophylaxis for arrhythmias in individuals who experienced a recent myocardial infarction.
Alright, switching gears and moving on to side effects! Beta blockers have plenty of side effects and they can be subdivided into two main groups, cardiac and extracardiac side effects.

Side effects8:37–9:38

Cardiac side effects include SA node depression that results in sinus bradycardia, heart block, and heart failure; while extracardiac side effects include fatigue, sedation, sleep disturbance, sexual dysfunction, dyspnea, and bronchospasm.
Bronchospasm is more common with non-selective beta blockers, such as propranolol, due to their effect on beta-2 receptors located in the lungs.
Moreover, beta blockers can lead to a condition called hypoglycemia unawareness. This is when an individual with diabetes, develops hypoglycemia but does not experience typical hypoglycemic symptoms which are mediated by epinephrine, like tachycardia, palpitations, tremor, and anxiety.

Contraindications9:38–10:33

As far as drug interactions go, class II antiarrhythmics should be avoided in individuals treated with calcium channel blockers, because of their additive effect on conduction velocity through the AV node.
Ultimately, this can result in AV block, which is a partial or complete disruption of electrical impulse conduction from the atria to the ventricles.
Moreover, class II antiarrhythmics, are contraindicated in the treatment of pheochromocytoma and cocaine toxicity because they can cause an unopposed alpha-1 agonism, which is excessive stimulation of alpha-1 receptors, due to blockade of beta-2 receptors on blood vessels.
This results in vasoconstriction and extremely high blood pressure, which may even lead to aortic dissection. Finally, the antidote for class II overdose includes saline, atropine, and glucagon.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Memory Palace10:33–12:39

So, we’re taking a road trip to see all the antiarrhythmic medications. The first stop was at the sea for the sodium channel blockers, and now we’ll make a pit stop at a blocked section of road for the beta blockers, which are the class II antiarrhythmics.
So let’s have two police officers trying to stop traffic on this section of the road and this will help you remember we’re talking about class II antiarrhythmics.
One of them has “β1“ on his uniform since he represents selective β1 blockers, and he has a trained police ArMadillo, since these medications start with a letter between A through M.
The other officer has just a “β” symbol since he represents nonselective beta blockers and he has a trained Kiwi from New Zealand, because these drugs start with a letter between N through Z.
Now instead of traffic cones, let’s use a long, purring cat to block off the road and it’ll help you remember these drugs prolong the PR interval.
So beyond the roadblock we can see there’s been some kind of incident and this area will contain the side effects. There seems to be a very sleepy man in his boxers standing in the middle of the street.
The boxers have little hearts on them to represent sexual dysfunction. He clearly just got out of bed, since he still has his blanket with him, which represents sleep disturbances.
However, there’s something weird going on since he’s wearing a very tight neck tie for bronchoconstriction, and there are empty honey jars around him that he has no recollection of eating, which stands for hypoglycemia unawareness.
For the cardiac side effects, he’s trying to hide a frozen heart behind him from the police, and this represents bradycardia.
He’s also carrying a heart shaped shield to deflect blame, which stands for heart block. All right, as a quick recap.

Review12:39–14:09

Class II antiarrhythmics, also known as beta blockers, bind beta adrenergic receptors, thereby preventing norepinephrine and epinephrine from binding them.
In pacemaker cells, they indirectly decrease the amount of calcium entering the cell at the end of phase 4, causing a slower pacemaker potential.
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 II antiarrhythmics are subdivided into selective beta-1 blockers, like atenolol, acebutolol, betaxolol, bisoprolol, esmolol, metoprolol; and non-selective beta blockers, like timolol and propranolol.
They’re primarily used to treat supraventricular tachycardias, such as atrial flutter, and atrial fibrillation, but also as a part of therapy and prophylaxis of arrhythmias in individuals who experienced a recent myocardial infarction.
Finally, side effects can be subdivided into cardiac side effects, like bradycardia, heart block, and heart failure; and extracardiac side effects, like sedation, sleep disturbance, sexual dysfunction, dyspnea, bronchospasm, and hypoglycemia unawareness.

Mind Map14:09–14:20

But wait, there’s 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.
Stay tuned for the answers after the credits.