Class III antiarrhythmics: Potassium channel blockers

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Introduction0:00–0:35

Antiarrhythmic medications help control arrhythmias, or abnormal heart beats. There are five main groups of antiarrhythmic medications: class I, also known as sodium-channel blockers; class II, also called beta-blockers; class III, also known as potassium-channel blockers; class IV, also called calcium-channel blockers; and miscellaneous antiarrhythmics, or unclassified antiarrhythmics.
Now, we’ll focus on class III antiarrhythmic medications. Normally, an electrical signal starts at the sinoatrial or SA node in the right atrium, then propagates out through both atria, making them contract.

Physiology0:35–4:14

The signal gets delayed a bit as it goes through the atrioventricular or AV node, then goes through the Bundle of His to the Purkinje fibers of both ventricles, making them contract as well.
When the signal doesn’t follow this pathway, we get abnormal heartbeats called an arrhythmia, and there are two main causes - abnormal automaticity and abnormal reentry.
Abnormal automaticity is when an area of the heart, say, a part of the ventricle, begins to fire off action potentials at a rate that’s even faster than the SA node.
As a result, 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. Alternatively, there can be an abnormal reentry which often results from scar tissue in a ventricle after a heart attack.
Scar tissue doesn’t conduct electricity, so the signal just goes around and around the scar, and each cycle can cause the ventricles to contract.
Alternatively, there might be an accessory, or extra pathway between the atria and the ventricles, like the bundle of Kent in Wolff-Parkinson-White syndrome.
Here, the signal might move back up the accessory pathway, since oftentimes it’s bidirectional, meaning the signal can go from atrium to ventricle as well as from ventricle to atrium.
This creates a reentry circuit that causes extra contractions that occur in between the signals coming from the SA node.
Now let’s focus on a single action potential in a myocyte - it can be broken into five phases. Here’s a graph of the membrane potential vs.
time. In phase 4, which is the resting phase, the myocyte’s membrane slowly depolarizes.
This is caused by the leakage of some ions - mainly calcium ions - through the gap junctions, which are openings between two neighboring cells, and that makes the membrane depolarize to the threshold potential, which marks the start of phase 0.
Phase 0 is the depolarization phase where voltage gated sodium channels open up when they reach the threshold potential, and they allow sodium to rush into the cell, creating an inward current.
This rapid influx of sodium causes the myocyte’s membrane potential to become more positive. After the membrane has depolarized, we enter Phase 1, initial repolarization.
At this point the sodium channels close and the voltage-gated potassium channels open up, allowing positive potassium ions to leave the cell.
This is called the outward current and the membrane potential starts to fall, and this creates a little notch on our graph.
Soon, there’s phase 2 or the plateau phase, which is when the voltage-gated calcium channels open up, and that allows positively charged calcium ions into the cell which counterbalances the potassium ions that are flowing out, so the membrane potential remains pretty stable.
During phase 3, or repolarization, the calcium channels close, but the potassium channels remain open, resulting in a net outward positive current.
At the same time, ion pumps start to pump calcium ions back out of the cell and that causes the heart to relax. Eventually the myocyte returns to the resting membrane potential and we start over with phase 4 again.

Mechanism of Action4:14–5:20

Now, class III antiarrhythmics bind and inhibit potassium (K+) channels, which are responsible for repolarization during phase 3 of the action potential in cardiomyocytes.
These channels are also called cardiac delayed rectifier potassium channels, or IKr. So, when they’re blocked, there’s less potassium leaving the cell, which leads to a slower rate of repolarization.
Ultimately, this results in the prolonged duration of action potentials and effective refractory periods, which is the period of time that the cell is unexcitable by new stimulus.
On the ECG, this shows up as a longer Q-T interval. So, longer repolarization prevents the fast conduction of the action potential throughout the heart, which eventually leads to a slower heart rate!
But, since class III antiarrhythmics prolong the QT interval, they can trigger a type of arrhythmia called torsade de pointes, which means “the twisting of points,” because the QRS complexes seem to twist around the isoelectric line.

Amiodarone5:20–6:51

Common medications in this class include amiodarone, dronedarone, sotalol, ibutilide, and dofetilide. First let’s focus on the most commonly used class III antiarrhythmic, amiodarone.
Despite being classified as a potassium channel blocker, or class III antiarrhythmic, amiodarone also blocks inactivated Na+ channels just like a class I antiarrhythmic; β-adrenergic receptors like a class II; and L-type Ca2+ channels like a class IV.
Its main mechanism of action makes it very useful in the treatment of most types of arrhythmias, including atrial fibrillation, atrial flutter, and life-threatening ventricular tachycardia.
But amiodarone contains a high level of iodine in its structure which makes it lipophilic and easy to deposit throughout the body.
This limits the use of amiodarone due to its toxicity and long half-life of 20-100 days. The long-term use of amiodarone can cause thyroid dysfunction, such as hypo- or hyperthyroidism; pulmonary fibrosis; liver dysfunction; neurological side effects, like tremor and paresthesia; constipation; corneal deposits; blue-gray skin discoloration; and photosensitivity.
On the flip side, amiodarone can still cause cardiovascular side effects such as bradycardia, heart block, and heart failure.
Due to numerous side effects, individuals on long-term amiodarone therapy should regularly check thyroid-, pulmonary-, and liver function tests.
Now, let’s move on to dronedarone, which has the same mechanism of action as amiodarone. But in contrast to amiodarone, dronedarone has a significantly shorter half-life (24 hours), since it doesn’t have iodine in its structure.

Dronedarone6:51–7:21

Thus it’s only used to treat atrial fibrillation and flutter. On the other hand, the lack of iodine makes it less toxic, therefore the most common side effect is gastrointestinal disturbance, such as diarrhea, nausea, abdominal pain, and vomiting.
Alright, now switching gears and moving on to sotalol. Besides being a potassium-channel blocker, sotalol is also a non-selective beta blocker, which means it can slow down the heart rate and decrease myocardial contractility.

Sotalol7:21–7:50

It can be used to treat life-threatening ventricular arrhythmias and atrial fibrillation or flutter. As far as side effects go, sotalol can cause a long Q-T and torsade de pointes, but it can also lead to bradycardia, hypotension, and lightheadedness.

Ibutilide and Dofetilide7:50–8:22

On to ibutilide and dofetilide! Both of these medications work as selective potassium channel blockers, but they differ on the route of administration and their indications.
Ibutilide is administered intravenously and it's used to treat acute atrial fibrillation; while dofetilide is taken per os, or perorally, and it’s used for prophylaxis and long-term treatment of atrial fibrillation.
Since they prolong the QT interval, the main side effect of these medications is torsade de pointes. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Memory Palace8:22–11:12

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, the second stop was at a blocked section of road for the class II, or beta blockers.
Next we’ll make a pit stop at a banana farm for the potassium channel blockers, which are the class III antiarrhythmics.
Let’s put 3 tall banana trees here to help you remember these are class III. For some side effects shared by all these medications, let’s have some long-tailed squirrels who are real cuties living on the trees to help you remember these drugs can cause a prolonged Q-T interval.
They are practicing rhythmic gymnastics with ribbons that resemble the ECG pattern seen in torsade de pointe. For the specific drugs in this class, let’s start with a robotic drone that’s harvesting the bananas and it represents dronedarone.
Next to it, there’s a confused toucan who’s asking, “Am I a drone too?” Now, the drone and the toucan are taking care of 3 baby chicks with the roman numerals I, II, and IV on their chest to help you remember amiodarone and dronedarone also share the same mechanism of action as drugs in those three classes of antiarrhythmics.
Now, let’s look at the side effects! The dronedarone drone is carrying a stomach-shaped sack for the bananas, and this represents the GI side effects like diarrhea, vomiting, and stomach pains.
For amiodarone, let’s give the toucan a lopsided bowtie, with a big lobe and a small lobe to represent hyper and hypothyroidism.
A spider is building a web on its chest for pulmonary fibrosis, and under the toucan, there’s a half eaten liver for liver damage.
One of the chicks has big sparkling eyes to represent corneal deposits and it’s sitting on a toilet since it’s constipated.
The next chick is sitting on a frozen heart for bradycardia, and his skin turned blue from the cold for the bluish-gray discoloration.
The last chick has bandages wrapped around its head to represent neurotoxicity and it’s chilling with a pair of sunglasses on to represent photosensitivity.
Moving on to the next drug! We have a banana harvester wearing stilts and he’s saying, “I’m so tall” for sotalol.
He’s trying to shoo away a large bee with the roman numeral “II” on its abdomen to help you remember that it’s also a beta blocker like the class II antiarrhythmics.
Finally, since ibutilide and dofetilide have “-tilide” in their name, let’s use a tilted baby banana tree to help you remember these medications are also potassium channel blockers.

Review11:12–11:59

All right, as a quick recap. Class III antiarrhythmics are also known as potassium channel blockers.
They slow down the efflux of K+ during phase 3 of the action potential in myocytes; thereby prolonging the duration of the action potential and effective refractory period.
On the ECG, this shows up as a longer Q-T interval. Class III antiarrhythmics include amiodarone, dronedarone, sotalol, ibutilide, and dofetilide.
Besides potassium channels, amiodarone and dronedarone also block Na+ channels and Ca2+ channels, as well as α- and β-adrenergic receptors; sotalol also blocks β-adrenergic receptors; while ibutilide and dofetilide are “pure” potassium channel blockers.
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.

Mind Map11:59–12:27

Stay tuned for the answers after the credits.
Class III antiarrhythmics: Potassium channel blockers: Video | Osmosis