Neuromuscular blockers

Definitions & Key takeaways

Neuromuscular blockers are medications used to relax the muscles during surgical procedures and mechanical ventilation. They work by inhibiting the actions of acetylcholine on nicotinic receptors at the neuromuscular junction. Inhibition of these receptors disrupts the transmission of nerve impulses to the muscles, thus causing them to become relaxed and unable to move.

Neuromuscular blockers are divided into non-depolarizing blockers, like atracurium, vecuronium, and rocuronium; and depolarizing agents like succinylcholine. Non-depolarizing blockers work by competing with acetylcholine for receptors. They are used in mechanical ventilation and to aid in surgery. On the other hand, depolarizing agents cause prolonged stimulation and subsequent desensitization of the receptors. They can facilitate tracheal intubation or short surgical procedures.

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Introduction0:00–0:14

Neuromuscular blockers are a class of medications that prevent acetylcholine from acting at the neuromuscular junction, which prevents the triggering of skeletal muscle contractions.
Okay, first things first. In order for a skeletal muscle to contract, your brain sends a signal, in the form of an action potential in an upper motor neuron.

Physiology0:14–2:20

The upper motor neuron then activates a lower motor neuron in the spinal cord. From here, the action potential is sent through an axon down to its ending branches, called axon terminals, to muscle fibers which they innervate.
The place where an axon terminal meets the muscle fiber is the neuromuscular junction. The neuromuscular junction has three main parts: a presynaptic membrane, which is the membrane of an axon terminal; a postsynaptic membrane, which is the membrane of a skeletal muscle fiber and is also called a motor end-plate; and a synaptic cleft, which is the gap between the presynaptic and postsynaptic membranes.
When an action potential reaches the axon terminal, synaptic vesicles that contain neurotransmitters, called acetylcholine, fuse with the cell membrane of the axon terminal, releasing the acetylcholine into the synaptic cleft.
The acetylcholine then diffuses over to the motor end plate on the muscle fiber and binds to ligand-gated ion channels, also called nicotinic receptors.
When that happens, these ligand-gated ion channels open up, letting lots of sodium ions rush into the skeletal muscle fiber, and a few potassium ions leak out of the cell as well.
But overall there’s an increase in positive charge on the inside of the muscle fiber causing it to depolarize. This causes the voltage-gated sodium ion channels on the membrane to open up, and there’s a huge influx of sodium ions into the muscle fiber.
This leads to a generation of an action potential, which rapidly spreads along the entire membrane, causing the whole muscle fiber to contract.
When the signal sent from the lower motor neuron stops, this causes synaptic vesicles full of acetylcholine to stop fusing with the membrane, while molecules of acetylcholine that are left behind within the synaptic cleft, are chopped up by an enzyme called acetylcholinesterase.
And muscle contraction stops. Alright, so neuromuscular blockers are medications that block the interaction between acetylcholine and nicotinic receptors at the neuromuscular junction.

Mechanism of Action2:20–2:39

This leads to skeletal muscle relaxation. And based on their mechanism of action, they’re classified into non- depolarizing and depolarizing blockers.
So, non-depolarizing neuromuscular blockers can bind to the same binding sites on the receptor as acetylcholine, but they don’t trigger the opening of ion channels.

Non-depolarizing Neuromuscular Blockers2:39–4:59

So when administered, they compete for these binding sites on the receptors, which leads to decreased depolarization of the muscle fiber and weaker contraction.
This group of medications includes atracurium, vecuronium, rocuronium, pancuronium, and tubocurarine; you can keep these organized because they all have -cur- in their name.
Clinically, they are usually used to relax the muscles before surgery or during intubation for mechanical ventilation, which is when someone is connected to a ventilator machine that helps them breathe.
They can also be used as general anesthetics during surgical procedures. So typically, non-depolarizing neuromuscular blockers are injected intravenously, and in less than a couple of minutes, they begin paralyzing small muscles of the face and fingers; then larger muscles in the neck, torso, and limbs; then finally, the diaphragm.
Gradually, in about 40 to 90 minutes, these muscles start recovering in the reverse order, so first the diaphragm, then the limbs, torso, neck, and then fingers and the face.
Now for side effects, they occur more frequently with atracurium. Specifically, atracurium induces histamine release, which causes bronchoconstriction, or narrowing of the airways; as well as vasodilation, or blood vessel relaxation; and thus causing hypotension, reflex tachycardia, and flushing, or reddening of the face.
At the same time, it produces a toxic metabolite, called laudanosine. Laudanosine is neurotoxic, so if it’s not properly excreted in the urine, like in individuals with kidney failure, it can build up in the blood and trigger seizures.
Now, reversal of these side effects can be achieved by giving cholinesterase inhibitors like neostigmine, which inhibit the degradation of acetylcholine by cholinesterase.
This raises the concentration of acetylcholine in the synaptic cleft, which will out-compete the neuromuscular blockers for the receptor sites.
Next, there are depolarizing neuromuscular blockers. What these do at first, is mimic the actions of acetylcholine; they stimulate the nicotinic receptors, opening up the ion channels, which leads to depolarization of the motor end plate.

Depolarizing Neuromuscular Blockers4:59–5:51

This may be seen as temporary muscle contractions, or twitching, known as fasciculations. And that’s Phase I, or the prolonged depolarization phase.
But the thing here is that these medications can’t be broken down by acetylcholinesterase in the synaptic cleft, so that depolarization goes on and on until the nicotinic receptors become desensitized, meaning it starts getting tired of responding and shuts down, letting the motor end plate repolarize, which allows the muscle relax.
This is known as Phase II, or the repolarization and desensitization phase. Now, the only medication still used from this group is succinylcholine.

Succinylcholine5:51–7:05

Clinically, it’s most often given in an emergency setting, when a breathing tube must be inserted quickly, or for short surgical procedures.
So once succinylcholine gets administered intravenously, its effects are seen in less than a minute. This effect lasts less than ten minute because it rapidly leaks into the plasma, where it gets broken down by another enzyme, called pseudocholinesterase.
In fact, certain individuals with a deficiency or reduced activity of this enzyme, will be more prone to accumulating succinylcholine, so they might not be able to use their muscles to move or breathe for hours after administration.
In other cases, succinylcholine might trigger malignant hyperthermia, which is a rare, life-threatening complication that involves extremely high fever and severe muscle rigidity.
Finally, prolonged opening of the ion channels of the nicotinic receptors during the depolarization phase lets a whole lot of potassium ions into the extracellular fluid, leading to hyperkalemia, and possibly, even serious cardiac arrhythmias.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Memory Palace7:05–9:28

So let’s go on a safari. One side of the park resembles the north pole, where we put the depolarizing medications, while the other side of the park is a desert for the non-depolarizing medications.
Okay, so on the desert side, we have a vet that cures the animals. He represents the medications that have -cur- in their name like atracurium.
Right now he’s intubating a giraffe that’s about to undergo surgery to help you remember their main indications. A stag with neon glow sticks on his antlers represent neostigmine, and it’s headbutting the vet to help you remember cholinesterase inhibitors like neostigmine can be used to reverse the effects of non-depolarizing neuromuscular blockers.
For side effects, let’s have some animals watch the procedure. These animals all love the vet and compete for his attention, which will help you remember that non-depolarizing neuromuscular blockers are competitive inhibitors.
There’s a snake going “Hisss” for histamine and it’s got red cheeks to represent flushing. Next is another giraffe with a neck brace for bronchoconstriction, and a bunny holding a heart for tachycardia.
Let’s put a kidney having seizures next to the animals to help you remember these medications have neurotoxic metabolites, and should be avoided in people with kidney diseases.
Okay, on to the depolarizing neuromuscular blockers! This area is where people come to rest and cool off from the safari, which helps you remember that these medications make the muscle fiber depolarize continuously until it gets tired, and needs a break.
So there’s a man sucking cola from a large straw for succinylcholine. The straw reaches all the way into his trachea to help you remember it’s also used for intubation.
For side effects let’s have a pile of bananas for hyperkalemia next to the visitors as their snack. Now, let’s have one of the resting men be frozen in a block of ice, where he can’t move or breath to represent the effect this medication has on people with pseudocholinesterase deficiency.
Next to him is a man on fire to represent malignant hyperthermia. All right, as a quick recap, neuromuscular blockers inhibit the actions of acetylcholine on nicotinic receptors at the neuromuscular junction, achieving muscle relaxation.

Review9:28–10:08

They are divided into non-depolarizing blockers, like atracurium, vecuronium, rocuronium, pancuronium, and tubocurarine, which compete with acetylcholine for the receptor and are used in mechanical ventilation and to aid in surgery; as well as depolarizing agents, like succinylcholine, which cause prolonged stimulation and subsequent desensitization of the receptors and can facilitate tracheal intubation or brief surgeries.

Mind Map10:08–10:36

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.