AssessmentsClass II antiarrhythmics: Beta blockers
Class II antiarrhythmics: Beta blockers
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A 15-year old girl comes to the office because of headaches, fatigue, reduced concentration, and dizziness for a year. She has also noticed that she has bouts of anxiety in the absence of triggers, and feels that she cannot digest her food as well as before. Due to the unspecific nature of her symptoms, she has been investigated extensively over the past year but both upper gastrointestinal endoscopy, and brain MRI have been normal. Her temperature is 36.8°C (98°F), pulse is 60/min, respirations are 18/min, and blood pressure is 85/55 mm Hg. When she stands up, she becomes tachycardic at a sustained pulse 130/min, at this time there is no change in her blood pressure. Which of the following therapeutic measures is most likely appropriate?
Content Reviewers:Yifan Xiao, MD
Contributors:Sam Gillespie, BSc
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.
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.
Now, in contrast to non-pacemaker cells, whose action potential has 5 phases, an action potential in pacemaker cells has only 3 phases.
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.
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.
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