Muscle Relaxants

Brown

Member
I was about to ask for a refresher on the cholinergic system, but since I'm here and nobody's added anything on the topic thus far, figured I might just add something to it. Hope I'll do it right.

First off, "muscle relaxant" refers to relaxing skeletal muscles, not smooth muscles. Why? Because the skeletal muscles are operated via nicotinergic acetylcholine receptors (ion channels!) whereas smooth muscles follow muscarinergic receptors. So muscle relaxant == substance that decreases the contraction within skeletal muscles. Good way to differentiate is to consider muscle relaxants as "myotonolytica" and antispasmodics as "spasmolytica".

They find their use to relax muscles in preparation of a surgery or to make intubation easier. Anesthetically, they take over the muscle relaxant properties of highly dosed narcotics, lowering the required dosage only to properly sedative levels. Cave: they do NOT block afferent signals, meaning the patient stays conscious and will register you ramming your intubation tube inside their throat! However, they do block the inspiratory muscles! Ventilation is required!

In terms of physiology: the myoneural junction releases acetylcholine with every AP. ACh docks onto muscular receptors and causes a depolarization via opening voltage gated sodium-channels. That depolarization causes potassium channels to open, creating an AP and triggering the liberation of Calcium which ultimately leads to the muscle contracting. Important to note is that both the nicotinergic receptor agonists and the antagonists block the neuromuscular transmission within the myoneural junction. Meaning we classify the drugs based on their targeting area (central and periphery!) and/or their working mechanism (depolarizing / non-depolarizing).

The substances are, to my knowledge, all quaternary ammonium compounds. This makes them hydrophobic by nature and is important for ther affinity towards the nicotinic receptor overall. Important substances include the alkaloids tubocurarine and toxiferine (derivate: alcuronium) and the aminosteroids vencuronium- and pancuronium bromide. All of them are acetates like acetylcholine. As liphophobic substances, they are barely resorbed within the intestines, meaning they are applied exclusively intravenously. Furthermore, being hydrophobic allows them to stay out of cells and to remain within the extracellular compartment.
Side effects include the liberation of histamine (Tubocurarine!) and co-activation of other cholinergic receptors (where antagonists express anti-cholinergic effects and agonists logically express cholinergic effects).

Periphery Nicotinergic antagonists like tubocurarine connect to the receptor WITHOUT activating it --> aka not causing it to open, hence non-depolarizing. They block an alpha-subunit of the receptor, preventing it from opening and triggering a muscular AP and, by extension, the muscular contraction. (Interesting side note: if you stimulated the muscle via a direct electric pulse rather than via the motor neurone, you can circumvent this blockade and still cause a regular contraction.) Important to note is the so-called Decurarisation which is fancy-talk for rendering ND-relaxants less effective via the usage of cholinesterase-inhibitors (Neostigmine, Distigmine, Sugammadex) which break the recycling of ACh, allowing it to compete longer for it’s own receptors. Substances: Tubocurarine, Pancuronium, Vecuronium, Micuronium, Alucuronium.

Nicotinergic agonists work more or less in the complete opposite way: they connect to the ACh receptor, open it and depolarize the end plate. Unlike ACh itself, however, they get processed a lot more slowly, leading the depolarization to last far longer. The nicotinergic receptors remain opened, however the potassium-channels in close vicinity to the end plate proceed to shift into their closed-deactivated state, preventing the depolarization to transmit into a muscular AP. So TL;DR: permanent depolarization with deactivation of the Na+channels that cannot be reversed via decurarisation. Substances: Suxamethonium (NB: far more undesired side-effects than the ND-Relaxants).

Substances: Tubocurarine (D), Alcuronium, Pancuronium —> 60-80m duration, 3-5m til full effect; T and A get excreted without modification, P eliminated via esterlysis. (NB: Alcuronium is eliminated over the kidneys —> much longer effect duration under kidney insufficiency!)
Vecuronium, Atracurium —> 20-30m duration, 3-5m til full effect; eliminated via ester-hydrolysis (NB: Atracurium is processed mainly via Hofmann-elimination. One product of this reaction, Laudanosine, can enter the CNS and cause spasms in higher concentrations.) Mivacurium —> 15-20m duration, 3m til full effect Suxamethonium —> 5-10m duration, 2m til full effect (NB: both M and S are eliminated via the enzyme butyrylcholinesterase, NOT via AChesterase! Hence the quick elimination)

Interesting: Before I mention the clinically more relevant group of central relaxants, a quick note onto botulinium toxine (botox!), which prevents the ACh from being released at the neuromuscular junction rather than blocking the nicotinergic receptor, however with the same results. Dantrolene, the most important substance to combat maligne hyperthermia, is also a honorable mention here, since it inhibits the electro-mechanical transmission by blocking the calcium-release within muscle tissue directly. Central relaxants do not block the signal transmission from nerve to skeletal muscle. Instead they inhibit the CNS directly from stimulating the muscles, causing a decrease in their tension. In analogy to agnostic and antagonistic effects at the myoneural junction, CRs express (ant)agonistic effects at their neuronal nicotinic receptors. They follow more of a case-by-case concept than the periphery drugs, so I only included a couple of clinically relevant substances.

Substances: (Overview) - Tizanidine (alpha2-Adreno-antagonist): eliminated via CYP1A2, 2-4hrs HLT, excretion mostly via kidneys, administered by mouth. Less side effects than diazepam or baclofen. IND: spasticity under neurological conditions (spinal chord injury, MS), painful spasticity (lumbago) SE: Dizziness, sedation, hypotension (a bit) and intestinal - Baclofen (GABA-b-receptor-agonist // CAVE: NOT GABA-a-receptor —> not suitable as Parkinson medication!): eliminated without metabolic change in feces, small part after deamination, administered by mouth. GABA-b-receptors express a higher stronger hyper polarization than GABA-a, resulting in the desired relaxant properties within spinal motor neurons. Cave: higher toxicity with severe side effects under sudden withdrawal! IND: spastic movement disorders, spinal chord injuries, MS SE: sedation, hyperacidity, ataxia, excitation under sudden withdrawal - Benzodiazepines: Diazepam and Tetrazepam, among others. Explaining these would probably bloat this summary’s volume into oblivion! - Ca2+/Na+Channel-Inhibitors: Tolperisone



Hope you guys can use and enjoy the little overview I made!

These substances tend to be explained very confusingly around here, so I thought I'll do us a favor and try to break it down one by one. Please let me know if I made any mistakes along the lines!
 

Atkinson

Active member
Would nicotine be considered a depolarizing agent, and bupropion and mecamylamine a non-depolarizing agent?

My understanding is that they can too easily enter the CNS (and I think they prefer these receptors, but I'm not sure how) and produce too much CNS effects to be used as muscular blockers.
 

Atkinson

Active member
In analogy to agnostic and antagonistic effects at the myoneural junction, CRs express (ant)agonistic effects at their neuronal nicotinic receptors.
You mean agonistic, or like a silent antagonist? Also, I don't think antagonizing central nAChRs are involved in muscle contraction/relaxation, and none of the drugs you list do it. I'm really confused here but I'm pretty sure I just misunderstood what you said lol.
 

Brown

Member
Yeah, that was phrased a bit more stupidly than intended!

Secreted acetylcholine creates the myoneural junction potential at the muscular nicotinic receptors, right? And nicotine - in analogy - creates an EPSP (excitatory post synaptic potential) at the neural nicotinergic receptors. Depolarizing agents fight with ACh over the end plate receptors, decrease the potential and inhibit the neuromuscular transmission in the periphery - which is what the central antagonists do with EPSPs instead of APs. They are ganglionic blockers - named because of historic reasons, but they really work for the entirety of the CNS. Bupropion is a NDRI (noradrenaline and dopamine reuptake inhibitor) - that has nothing to do with nicotinergic receptors to my knowledge. It probably tampers with the "reward" mechanism when it comes to breaking nicotine addiction. Still, NDRIs operate on an entirely different mechanism when it comes to Parkinson, depression or ADHD - or any other condition I might be forgetting! Mecamylamine on the other hand is a central nicotinergic receptor antagonist, a ganglionic blocker. The working mechanism stays true to it's name, as the antihypertensive effect is achieved via blocking the autonomic ganglions, as blood vessels are coordinated mostly by the symapthicus and a ganglionic block thus leads to vasodilatation. There are far better alternatives in this regard however, so yes, as you correctly said: they aren't in use anymore.
 

Brown

Member
Also, I don't think antagonizing central nAChRs are involved in muscle contraction/relaxation, and none of the drugs you list do it. I'm really confused here but I'm pretty sure I just misunderstood what you said lol.
They do! Just completely differently from peripheric muscle relaxants, as they're only indicated for treating muscle spasticity (excluding the Benzodiazepines, which outright cause muscle relaxation throughout the bank).
 

Adams

Well-known member
Oh, are you talking about spasmolytics, like M1 muscarinic acetylcholine receptor antagonists (like atropine)? the ones you listed don't block acetylcholine receptors but atropine-like spasmolytic?
 

Barnes

Active member
Bupropion is a ganglionic blocker like mecamylamine in addition to its NDRI effect. I'm not clear on what you're saying here though; are ganglionic blockers and agonists also neuromuscular blocking agents? I believe they also work on muscular junction receptors, just to a lesser extent (whereas typical neuromuscular blocking agents only work on peripheral receptors).
 

Brown

Member
Spasticity =/= spasm! Spasticity is within skeletal muscles, which is why I included them alongside benzodiazepines, which work just as fine as spasmolytics.
 

Brown

Member
Are ganglionic blockers and agonists also neuromuscular blocking agents?
They decrease tension in every (para)sympathically connected organ and subsequently decrease tension in the muscular system (They don't attach directly into the periphery, they operate by manipulating the CNS directly), though not every ganglionic blocker expresses these functions, which might be why you're confused here - and what I could probably have written better to begin with.
 

Atkinson

Active member
Maybe thats how they produce that particular effect, but overall both non-depolarizing neuromuscular blocking agents and ganglionic blockers work by antagonizing nicotinic acetylcholine receptors. On the other hand, depolarizing neuromuscular blocking agents and nicotine both activate nicotinic acetylcholine receptors. I don't think either are truly selective for one type over the other (ganglionic for mecamylamine, nicotine, and bupropion and neuromuscular junction for tubocurarine and other neuromuscular blocking agents), but rather just prefer one somewhat, and neuromuscular blocking agents can't cross the blood-brain barrier.

So is whatever I just said correct?

Sorry it might be somewhat incoherent lol.
 
Groups of muscle relaxants: 1.) central acting muscle relaxants (Baclofen, Benzodiazepines, Tizanidin, Tolperison) 2.) peripheral acting muscle relaxants 2a) myotrope muscle relaxants (Dantrolen) 2b) neromuscular blockers the 2b) neuromuscular blockers can be further divided in x) depolarizing muscle relaxants (only one in clinical use is Suxamethonium) y) non-depolarizing muscle relaxants (all the others like Pancuronium).


As Atkinson said neuromuscular blockers only act peripherally, thats already indicated by their name suffix -ium, which shows the permanently cationic (positively charged) nature of such compounds as Suxamethonium, Alcuronium and Pancuronium.
 
Thanks for writing that Chapter Brown.

Though you might have to rewrite some parts. "The substances are, to my knowledge, all quaternary ammonium compounds. This makes them hydrophobic by nature and is important for ther affinity towards the nicotinic receptor overall. " That for example. Only the neuromuscular blockers are quaternary ammonium compounds. The ionic nature makes them more hydrophilic, not hydrophobic actually. They are imitating Acetylcholin, which is also a quaternary ammonium. So that positive charge is required for the receptor affinity. Also they can not pass blood-brain barrier because of it.
 
Also Sugammadex is not an AcetylCholin-Esterase-Inhibitor (AChE-I), but a special cyclodextrine. It is designed to bind Rocuronium and Vecuronium.
 

Atkinson

Active member
So are mecamylamine and nicotine also sorta neuromuscular blockers? They just act too much centrally to be useful.
 
So are mecamylamine and nicotine also sorta neuromuscular blockers? They just act too much centrally to be useful.
No see, nicotine doesn't have the properties needed to be a depolarizing relaxant. Depolarizing muscle relaxants act via high frequency depolarization. The ACh-Receptor gets desensitized because he is constantly being activated. Those kind of muscle relaxant bind with high affinity and for a long time. Nicotine has effects via activation of the Receptor. Meaning nicotine binds and unbinds from the receptor easily and doesn't desensitize it.
Well, on Wikipedia it says it acts thru depolarization block. But that's for high concentrations I guess.
I think the toxicity of nicotine could come from ganglion blockage.
 

Atkinson

Active member
Oh, so the deciding factor here is how long it takes for the agonist to dissociate from the receptor (K_off)? but could this be compensated for by increasing the dose or concentration sO that it'll be constantly activated anyways.
 
Yes, I mean Nicotine is also a Ganglionic blocker.

It will be constantly activated for a short time, until the receptor just cant be activated anymore (depolarization block, desensitization, or whatever you wanna call it).

That's why those cant be reversed with AChE-Inhibitors.
 
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