What's up Ninja Nerds? In this video today we're going to be talking about cholinergic agonists, also known as parasympathomimetics. Heck of a name. But if you guys really want to understand this video, you guys really want to get into this, I suggest going down in the description box below. We'll have a link to our website.
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We have a lot of cool things to offer there. All right, let's start talking about the cholinergic agonists. cholinergic agonist. Before we do that though, we have to understand a little bit about the kind of cholinergic system, if you will.
So we talk about the cholinergic system, it's the system where the neurons are particularly releasing acetylcholine. Now, without us getting really, really down the depths of this, you guys can really, if you want to understand a little bit more, we have a video on cholinergic receptors in our autonomic nervous system where we go over this, all the physiology in more detail. For here, we're going to break it down a little bit more simply.
What I want you guys to remember is When we talk about cholinergic pathways, this is, I think, the best at understanding the pharmacology aspect. So we have a bunch of different cranial nerves, and those cranial nerves, particularly some of them, have parasympathetic fibers. And what I want you guys to remember is that these parasympathetic fibers innervate particular target organs. Some of those, particularly cranial nerve 3, you know cranial nerve 3 supplies particularly like the eye, so particularly like you have what's called the.
extra ocular muscles. Well, it even supplies some of the structures inside of the eye, like the ciliaris and the pupil muscle. So here we have a parasympathetic fiber that's supplying the pupil. And you know what it actually does to the pupil? It causes pupillary constriction.
That's a normal type of function. We give it a special name. We like to be all bougie and stuff.
So we'd like to call it meiosis. All right. So it plays around with what's called meiosis, which is basically a fancy word for pupillary constriction. It also kind of moves the ciliaris muscle, contracts it, which also helps to be able to play a role in what's called accommodation, which is kind of changes in our vision, kind of like distances.
Okay, so it also plays a role in accommodation. Now, the next thing is we also have another particular cranial nerve. So we have cranial nerve three, which is a parasympathetic nerve and it has cholinergic types of fibers. The next one is particularly going to be cranial nerve seven.
So cranial nerve seven, also known as the facial nerve, also is going to be a nerve that goes and supplies our lacrimal glands. and also supply some of the salivary glands, like the submandibular salivary glands, sublingual salivary gland, and even some of the pterygopalatine glands as well. But the whole point is that it plays a role in what's called lacrimation, so the production of tears.
And it also plays a role in some of the salivation process. So salivation. Now there's another nerve that also plays a role within salivation, and that's actually going to be the glossopharyngeal nerve. So we'll have the glossopharyngeal nerve, or cranial nerve 9. And then you have another cranial nerve which we'll talk about called cranial nerve 10. But cranial nerve 9 also plays a role within salivation, but primarily via what's called the parotid glands.
All right, so the next thing that I want you guys to remember is we have cranial nerve 10, which is the vagus nerve. Now, the vagus nerve also has lots of cholinergic fibers that actually work particularly on some of our viscera, such as the heart. And when it works on the heart, it acts on what's called a negative chronotropic agent. So it helps to be able to slow down the conduction of the heart.
And we call that... Potentially when it's working on what's called the AV node, slowing down that conduction, it'll basically decrease your heart rate. So the one thing that you'll see with this one is what's called bradycardia.
Now one of the things that we know is without slowing down our heart rate, we could potentially slow down our cardiac output. Because we know cardiac output is equal to heart rate times stroke volume. So we can see both a decrease in heart rate and maybe a subsequent drop in our cardiac output.
So that's an important thing. The next thing is also in innervates, particularly the smooth muscle of our bronchioles. And what it wants to do is, when you have the smooth muscle of your bronchioles, generally the sympathetic nervous system, you want them to dilate.
Within the parasympathetic, you want them to constrict. So it'll actually induce what's called bronchoconstriction. So it'll induce what's called bronchoconstriction.
So it'll kind of make the actual airways a little bit smaller, narrowing the amount of air getting in. Okay, because you know when you're in the resting, digesting, kind of relaxing type of state, you don't want to be utilizing a lot of energy and doing a lot of things. So that's why we don't really need a ton of airflow when we're resting and digesting.
The next thing is our vagus nerve also helps to innervate parts of our GIT, but on the upper parts of the GIT. So the stomach, the duodenum, other parts there. And it helps to be able to promote secretion.
So it actually helps to stimulate what's called hydrochloric acid production by the stomach and some of the secretions of particular molecules within the intestines. So one of the things that we'll see is we'll see GI secretions, but it also loves to cause the contraction of the smooth muscle of the GIT. And so we'll see a lot of what's called increased motility of the GIT as well, so peristalsis. In the same way, this is all of your cranial nerves.
We have what's called the parasympathetic fibers from the sacral. part of our spinal cord, you know, from generally like S2 to about S4. We'll have these parasympathetic fibers that can come from that part of the spinal cord and then go and deliver parasympathetic or cholinergic fibers to other target organs in our actual lower part of our abdomen and pelvis, particularly the lower parts of the GIT. And again, works to be able to increase motility and defecation, right?
And then for the actual general urinary tract, it works in the bladder, the detrusor muscle. to be able to cause an increase in motility of the detrusor muscle to be able to empty urine. So these are important when you think about this with respect to these types of functions of the parasympathetic nervous system.
Now, the other thing that's really interesting is that we have another type of cholinergic pathway, but it's not a part of the parasympathetic nervous system. It's actually part of the sympathetic nervous system. So I kind of want to give you a different color here. So in the sympathetic part, which is like T1 to about L2, we have sympathetic fibers.
And what these sympathetic fibers do is these actually go and supply. So there's acetylcholine that's actually released in your preganglionic fibers. We already know that.
If you guys want some recap on that, go watch our cholinergic videos and our autonomic nervous system videos. But we know in all the preganglionic synapses, acetylcholine is released. In all of these postganglionic synapses, acetylcholine is released for this part of the parasympathetic nervous system for the craniosacral outflow.
But there's one other area. And the sympathetic part of the spinal cord, generally from about T1 to about L2, this is where the sympathetic outflow is. And the preganglionic fibers release acetylcholine, and generally, the postganglionics release norepinephrine for a sympathetic.
In this case, we don't. And this actually goes to the skin. This is one of the few examples where the postganglionic and preganglionic fibers of the sympathetic nervous system release acetylcholine and act on the skin. And this will actually induce something called sweating. So what I want you to remember is that the cholinergic pathway with respect to this part here can cause pupillary constriction, change in the actual visual kind of like near or far vision, lacrimation, salivation, cause lower heart rate or bradycardia, can cause bronchoconstriction, can cause an increase in GI secretions and motility and inducing defecation, and cause increased motility or contraction of the bladder causing urination, and sweating.
These are important concepts. Now, but there's one more thing that we have to talk about, and it's a big one, because this is a part of like our autonomic nervous system. There's also something for the somatic nervous system.
You know what else is really interesting? There's also cholinergic pathways that act with, particularly within the cerebrum. And within the cerebrum, we're not gonna go crazy down this rabbit hole, but within the cerebrum, there is also cholinergic pathways that play a role in cognitive function. And so as we have patients who potentially get older or suffer from very specific diseases, they may have a decrease in this acetylcholine pathways within their central nervous system and potentially develop something called Alzheimer's or decreasing memory.
And so it's important to remember that these are a lot of the functions that this has to do with. Now, here's what's really cool. When we talk about the cholinergic system, the drugs that we're going to be giving people, they're particularly working at these target sites. And you know what's really interesting is we'll zoom in on this, but imagine here we're going to release acetylcholine and acetylcholine is going to have to work on this pupil or on the ciliaris muscle.
How the heck does it do that? It has to have a particular receptor. And that's what we'll talk about next because what happens is certain drugs that we give can act on the receptor and potentially act like acetylcholine, stimulating the receptor, causing all of the same mimicking type of effects.
Or we can have another drug that can actually work to increase acetylcholine levels, not by directly stimulating the receptor. They can just increase acetylcholine levels by... preventing a particular enzyme from breaking it down called acetylcholine esterase.
And we'll talk about that. Before we do that, let's talk about the last function of the actual cholinergic system. All right.
So the next component here that we have to talk about is that the cholinergic pathway is also involved in what's called our somatic nervous system. So we talked a lot about our autonomic nervous system, some of the actual central nervous system pathways in the cerebrum, but we also have acetylcholine particularly released from these somatic motor neurons. And what happens is this acetylcholine that we actually release can act on skeletal muscles. So a lot of things that we were talking about up here with acetylcholine and working on our target organs up here was about smooth muscle, cardiac muscle, glands, thus being a part of the autonomic nervous system or other types of neurons in the central nervous system.
For here, we're having it work on skeletal muscles. And what you guys need to know is that this helps to be able to produce skeletal muscle contraction. So what this will do is cause contraction. of the skeletal muscles.
So this is an important concept, and we'll actually go into a little bit more detail about how acetylcholine particularly works on... these target organs because what you need to understand is there's different types of receptors. In order for acetylcholine to exert its effect, we know based upon the concept of pharmacodynamics that a drug will potentially need some type of receptor to be able to bind to to produce its type of cellular response. Well, in this situation here for the skeletal muscles, it's what's called nicotinic receptors. These are ligand-gated ion channels.
For all of these up here, they're likely all going to be what's called muscarinic receptors. And these are called G-protein coupled receptors when it's acting on the target organs. So generally, nicotinic receptors are located in two particular places. One is on the skeletal muscle, what's called the neuromuscular junction, neuromuscular junction here.
And the other one is right here at these preganglionic sites. So the point where between you have your preganglionic neuron and your postganglionic neuron, we also have what's called nicotinic receptors. But generally at all these target organ sites.
They're going to be muscarinic receptors. All right, so now let's go ahead and take a look at these types of receptor pathways and going over how particular drugs are targeting specific receptors or specific enzymes involved in the actual acetylcholine and its response at the receptor site. All right, guys, so now what we need to do is take a look here.
Let's actually zoom in. Imagine that we have here a target organ, if you will. Okay, so let's say that this is actually that somatic nervous system connection, right?
So you have the... somatic neuron releasing acetylcholine on the actual skeletal muscle cell. So this is going to be our skeletal muscle cell. This is going to be our muscle and particularly the skeletal muscle.
What I want you guys to understand is how does this actual acetylcholine process work? Because what we need to understand is whenever we have acetylcholine particularly being released, all of this acetylcholine pathway acting on the receptor producing its response, where do drugs come into play to work in this concept? And then we'll do the same thing Where we say, okay, let's take a look at muscarinic receptors, the ones that are inhibitory, the ones that are stimulatory, have a good understanding of that, and how do drugs actually come into play within that system? Alright, so first thing, whenever we have acetylcholine, how do we actually make it?
Well, you know there's a molecule called choline that we actually get from our diet. So choline is something that we get from our diet, and we have special transporters that will bring the choline into the actual synaptic neurons. Then...
You know we have mitochondria, right? Generally, the mitochondria are important because they actually have these very special molecules here called acetyl-CoA. And what we'll do is we'll take acetyl-CoA and we'll combine it with the actual choline. And when we do, we use this special like little pink cute enzyme here called choline transferase. It's a choline acetyl transferase.
And what it'll do is it'll take all of these things, combine them together. So we're going to have choline combined with the acetyl-CoA. And what we're going to do is we're going to make acetyl-Coline.
And we're going to put this into these beautiful little vesicles here. So now out from this enzyme, we're going to make acetylcholine and put them into these vesicles. Now what happens is, once there's some particular stimulus, let's say for whatever reason, this neuron becomes activated.
And action potential moves down the somatic neuron. When action potentials move down the somatic neuron, what do you guys know about that? You guys know that it actually opens up what types of channels on the synaptic neuron. You guys know this, come on. This would be our voltage-gated calcium channels.
And what happens is calcium will rush into this particular synaptic neuron, and what it'll do, it'll actually help to be able to stimulate the fusion of the actual vesicles containing acetylcholine with the actual membrane of the synaptic terminal. And then via what's called exocytosis, we'll release our acetylcholine molecule out into the synapse. Now once it's out there, acetylcholine sees, we're going to draw it like here, it's like this little dot here, so it's going to be, this is acetylcholine. Acetylcholine will come and bind onto these little like pockets on these little receptors.
What are these receptors here called? I know you guys know it. This is called a nicotinic receptor.
And what I want you guys to remember, if you guys remember from the pharmacodynamics lecture, that nicotinic receptors are what's called a ligand-gated ion channel. So they're a protein channel. They have a little pocket where acetylcholine will bind. Now normally these channels are kind of closed. closed because there's no ligand bound to it.
And so imagine that there's like a little gate here blocking this off. So imagine it's like this. But once the acetylcholine binds with the actual little pocket there, it opens up the gate for all of these.
and now this gate's open which it used to be prior closed. What's going to start moving in? Sodium ions will start rushing into the actual muscle cell. As sodium ions rush into the muscle cell it starts making the inside of the muscle cell positive depolarizing the actual muscle cell. And what we know is that as we depolarize the muscle cell we'll activate that whole sarcoplasmic reticulum, release calcium cause the whole cross bridge.
We already know this. But we'll induce a muscle contraction. That's the whole process.
Now, after we've stimulated the muscle to contract, what has to happen? We need it to relax, baby. So how do we get that bad boy to relax? Get acetylcholine out of there. So what happens is in order for acetylcholine to not be present, we got this enzyme here.
You see this like dude with a honking nose right there? This enzyme here is called acetylcholine. Esterase, one heck of a name. But what this acetylcholine esterase will do is, it'll actually break down the acetylcholine. And when it breaks down the acetylcholine, so here's the acetylcholine, it'll get broken down by this particular enzyme into those constituents.
specifically choline like the acetyl groups so now it's rendered ineffective we can't utilize it anymore and so the acetylcholine levels within the synapse drop and then now the muscle will no longer contract that's an important concept because we can actually utilize drugs to protect Potentially work at this actual nicotinic receptor maybe act like acetylcholine You know we have drugs potentially that can act like this and bind that little pocket open up these channels and have ions flood in induce contraction or We can have drugs particularly that work and what would they what would you want to do think about this? This guy works to be able to break down acetylcholine if I want to give drugs that act like acetylcholine What would I want to do? I'd want to try to indirectly maybe increase my acetylcholine levels by inhibiting acetylcholine acetylcholinesterase. If I inhibit acetylcholinesterase, will I break down acetylcholine?
No. What will happen to the acetylcholine levels in the synapse? They'll increase, and it'll act just like as though I'm stimulating that actual receptor.
Okay, the next concept here is we have this same thing that we're going to go over, but we're going to go over this with muscarinic receptors. This is the same concept, so we should actually be very quick with this. We take what? Choline. We bring choline, we're only going to do it from one side here, into the actual synaptic terminal.
terminal. It combines with acetyl CoA. Acetyl CoA whenever it combines with the choline will get converted into acetyl choline via this enzyme, the choline acetyl transferase, put into the synaptic terminals.
An action potential moves down the axon. When an action potential moves down the axon it does what to the actual terminal here? Activates these special channels here called voltage gated calcium channels. Calcium channels open, they flood into the actual synaptic terminal.
and stimulate the fusion, which leads to what type of process? The synaptic vesicles fusing with the actual cell membrane and releasing the actual acetylcholine via exocytosis. Now, once the acetylcholine is released via exocytosis, it can act on receptors.
In the same way it acted over here by the nicotinic receptors, we can have it act on muscarinic receptors. What I want you to know is this could potentially be a muscarinic receptor. Let's say, I'm going to give you an example.
Generally, the muscarinic receptors that are inhibitory. So we have particularly muscarinic receptors that are inhibitory. So we're going to have inhibitory receptors, if you will. They're going to try to be able to slow things down, inhibit things.
This means... means it would work through a very special type of G protein coupled pathway. You know what that G protein coupled pathway is called?
This is called the G inhibitory pathway. And the primary, there's a lot of muscarinic receptors, but the primary one that I want you to remember that inhibits is the M2 receptor. In some degree, M4 receptors, but I don't want to make it too complicated. M2 receptors is the one that I want you to remember. Now, how does this happen?
Acetylcholine, here it is. right, we're going to have acetylcholine working on these two sites here. So acetylcholine will come over here and bind on to this receptor. When it binds on to this G protein couple receptor it changes its shape. When it changes its shape it activates a protein here called a G protein and this is a G inhibitory protein.
We know that that will release GDP and be stimulated by GTP. So we know GTP will actually bind to this. When GTP binds to this it then becomes active and moves along the the cell membrane and works on an enzyme called adenylate cyclase.
But what would it do to adenylate cyclase? This is a G inhibitory. It'll inhibit adenylate cyclase. He's normally supposed to take ATP and convert it into cyclic AMP, which helps to be able to activate protein kinases. But in this situation, you know what protein kinases are supposed to do?
They're supposed to phosphorylate proteins to perform specific actions. But what we're going to do here is we're inhibiting this enzyme. It's not going to perform this function.
So it's not going to make ATP. into cyclic AMP. We're not going to get protein kinase A.
And therefore, because of that, we're going to get a decrease in the phosphorylation of particular proteins. So all this phosphorylation reactions that are supposed to work on particular proteins, we're not going to get. You know why this is a great example? Because in our actual heart muscle, particularly the actual nodal cells of our heart, this is important because We have specific channels that we want to phosphorylate to be able to open up and allow for ions to flow in, right, like calcium or sodium. And these are supposed to be phosphorylated in order to do that.
If we don't phosphorylate these, they're not going to open up and allow for ions to be able to flood into them. And we won't be able to stimulate this actual nodal cell, the AV node. You know what else is really cool? G-inhibitory protein, know what else it actually does?
There's three units of it, three subunits. There's an alpha, a beta, and a gamma. What happens is this G-inhibitory subunit, the actual beta and gamma subunit, can actually bind on to potassium channels.
Now, you're like, what the heck? Potassium channels? Where did that come from? When it binds on to these potassium channels, that G-inhibitory, like the beta gamma subunit, it'll bind on to this little part here.
So here's going to be the part of that G-protein, some part of it, the beta gamma subunit. When it binds on to it, it opens up these channels and allows for potassium ions to leave the cell. If potassium ions leave the cell, what happens to the inside of the cell?
the cell. It becomes negative. If you make the inside of the cell negative, what do you do to its actual activity?
You decrease it and now won't be able to generate action potentials. This is a perfect example of what type of tissue over here where we wanted to slow things down. The AV node, the heart to lower heart rate.
So this would be a great example of an AV nodal cell. So if I gave a particular drug that act like a as a direct agonist on that muscarinic receptor, what would be the overall response? It would inhibit this particular cell from functioning.
Or if I gave a drug that worked, again, that same concept, the acetylcholine esterase, I inhibited it, caused an increase in acetylcholine, the increase in acetylcholine will stimulate an increase in this particular pathway, causing the inhibition of that cell. It's the same kind of concept. Now, the other types of cells that are actually going to have receptors that are stimulatory, stimulatory receptors, there's...
There's a bunch of these. I don't want us to get lost down the rabbit hole. What I want you to remember is that these are usually coupled to GQ and some degrees G-stimulatory proteins, but I want you to primarily remember GQ proteins.
And the primary one that I want you to remember is M3 receptors, muscarinic type 3 receptors. Technically, M1, M3, M5, but M3 is the most important one. So M2 is the most important inhibitory one, M3 is the most important stimulatory one. It's the same concept. Acetylcholine binds onto this receptor, changes its shape, activates a G protein, so it gets rid of a GTP, binds a GTP.
When it becomes stimulated, activates an enzyme. This is called phospholipase C. Phospholipase C will break down parts of the cell membrane, a molecule called PIP2, and break it down into something called a cell.
DAG, which is called diacylglycerol, which activates protein kinase C, and IP3, which works to be able to increase the calcium outflow from what's called our... sarcoplasmic reticulum or from the endoplasmic reticulum. And the whole concept is that if you have an increase in protein kinase C and an increase in calcium, you're going to be able to cause a lot of phosphorylation of particular types of proteins and increase the activity of these particular proteins, increasing the response.
For example, let's pretend that this is a smooth muscle cell. muscle of the GIT. Acetylcholine gets released, activates this M3 receptor, increases the activity of the phospholipase C, increases diacylglycerol, increases IP3.
If you increase these, they're going to activate protein kinase C, increase calcium levels. Protein kinase C will phosphorylate particular channels to bring more positive ions into the cell. If I bring more positive ions into the cell and I cause the inside of the cell to become very positive, what am I going to do to the inside of the cell? make it depolarize and then subsequently contract.
And that would increase the GI motility. So you understand where the difference comes in between these. All right.
So if I gave a direct agonist to act on this muscarinic receptor, it produced the same exact response. Or if I gave a drug that inhibited this acetylcholine esterase, it would increase acetylcholine indirectly and give the same type of response. Because again, what happens to the acetylcholine? It gets broken down by this molecule into what's called choline and then it's acetyl group. product and gets recycled and that's via this acetylcholine and I'm just going to put esterase.
So that leads us to the next point. What are the drugs that I can actually give to work as direct agonists on either a muscarinic receptor or a direct agonist on the nicotinic receptor and what are the drugs I can give to inhibit the acetylcholine esterases to increase the acetylcholine and still produce the same type of effect? Let's talk about that now.
All right so when we talk about these let's make sense. The direct agonists, they're going to work either directly at the muscarinic receptor or directly at the nicotinic receptor. So which are the ones that are actually going to be direct agonists? So I want you to remember bethanacol, methacholine, pilocarpine, and carbacol.
Now, bethanacol, methacholine, and pilocarpine, it's actually nice, thank goodness. They all work on muscarinic receptors only. So what I want you to remember for these is that it works only, all of these.
Let's actually do it like this so we can save ourselves some. Time and pain here is that all of these work on muscarinic. receptors. And the type of muscarinic receptor they work on depends upon the target organ or their indication that we'll talk about later. For example, bethanacol may work very heavily on M3 receptors because it loves to cause an increase in GI motility and detrusor activity.
Methacholine loves to act on particularly types of M3 receptors and cause bronchoconstriction. Pylocarpine may act on some of the M3 receptors as well. And carbacol, what about this bad boy? This one can actually work on both.
This is the only one that acts on the muscarinic, dang thing, I can't spell these dang things, muscarinic and nicotinic receptors. So it's actually relatively easy to remember your direct agonist, right? And which ones work on the muscarinic?
Pretty much all of them except carbacol, which acts on our nicotinic receptors and muscarinic receptors, which is actually nice because we never really use carbacol anymore anyway. But We've got to learn about it. The next concept here is the indirect agonist.
These are the ones that are working what way? Again, when we talk about these, you're particularly working to stimulate the muscarinic receptors. These were those G-protein coupled receptors.
You're trying to stimulate these bad boys. For this one, you're trying to work on the G-protein coupled receptors, stimulate them. But you're also trying to stimulate the nicotinic receptors as well. For this one over here, they don't even work on the dang receptors. They work on that cute little enzyme, that acetylcholine esterase enzyme.
And because of this one, what we need to be able to understand is that we know that all of these are going to work on the acetylcholinesterase. But what's an important concept to understand is which ones will actually inhibit this particular enzyme to where it's reversible. So it's reversible.
meaning if I inhibit this enzyme, there is a possibility that it'll stop inhibiting it. That's an important concept, okay? Because if we can't reversibly uninhibit that enzyme, then we're going to have some serious problems. And that's one of the dangerous things that the military system has actually utilized with this last one, or the types of categories in this.
But whenever you have something that's reversible, it also determines its kind of onset or length of action. For example, edrophone. Idrophonium is very short, so very short acting.
Doesn't last very long. Maybe like honestly up to a minute max. Fisostigmine, neostigmine, those are also relatively kind of like shorter acting as well.
But one of the big things is like peridostigmine. Peridostigmine, this one is actually like relatively in comparison to all of these. Idrophonium, fisostigmine, neostigmine, peridostigmine.
It's probably one of the longer lasting ones. The other thing that's also important to remember is that fisostigmine, denepazil, and rivastigmine are all what's called tertiary amines. So let me actually write that down. So fiso, I'm going to put fiso, and denepazil.
and rivastigmine are all what's called tertiary amines, meaning they are very highly lipid soluble, meaning that these can penetrate into the central nervous system, increase blood-brain barrier penetration. And that's an important concept. So these are particular drugs that maybe denepazil, rivastigmine, and another drug called glantamine are very good for penetrating into the central nervous system for maybe cognitive function types of things. For example, Alzheimer's, where they have a decreased...
and cognitive function due to a decrease in their acetylcholine pathway. If we increase the acetylcholine within those actual central nervous system pathways, we could actually improve some of their cognitive function. And these would be good drugs. Fisostigmy, not necessarily that good at that, but you get the point.
All right. So reversible indirect agonist is going to be this particular group. Big things to remember, edrophonium, very, very short acting. Pyridostigmine is the longest acting in comparison to edrophonium, physostigmine, neostigmine, and pyridostigmine. And then physostigmine, denepazil, rivastigmine, and another drug called galantamine are highly lipid soluble because they're tertiary amines so they can cross the blood-brain barrier.
The last one is ecothiopate or any other kind of things that are similar. to this. One of the scary things of a similarity, so similar kind of like drug class, so within this, think about the drug called sarin, which is that nerve gas, or any kind of pesticide or organophosphates, they act like this drug.
This was a drug that we actually utilized in glaucoma, but we don't utilize it anymore because of its severe side effect profile, and we had better drugs. What the fearful thing about these types of drugs, especially things like sarin or pesticides or ganaphosphates and things like that, is that these are irreversible. So these are irreversible inhibitors of that cute acetylcholinesterase enzyme.
So you won't be able to uninhibit them. And that's a very scary thing because what happens is what these drugs will do is They'll put something called an alkyl group on this enzyme. So imagine that you put like this alkyl group. Here's the alkyl group, and it kind of inhibits the enzyme. It prevents it from being able to perform its function.
What happens is certain other enzymes may come in and remove that alkyl group. That's a problem. If you do that, let's say that we actually go from this point where it has the alkyl group, and then what you do is you remove a piece of it. You remove a piece of the alkyl group.
That piece is actually, if we have to reverse this drug, for whatever reason because of toxicity. If we remove a piece of that alkyl group, so Natalie has this, this is a very dangerous situation. We can never go back to this point here. If a patient gets a drug like sarin or an organophosphate type of thing or a pesticide or eclothiophate and they start developing toxicity because of it, so cholinergic crises types of effects, if we give them the antidote, the pralidoxime, at this stage when they have the alkyl group on them, they would actually be able to be reversed. But what happens is the special types of like phosphorylating enzymes come in here and lay down some phosphates onto this and remove a piece of the actual alkyl group.
Now, this can't be reversed. So you can give them pralidoxine, but it will not work. This is an important concept they may ask you on your exam.
And this is called aging. I'm not even kidding. It's literally called aging.
So if you give the actual antidote whenever the enzyme is in the aging state, It will not be reversed and it'll continue with the cholinergic crisis, meaning that you've removed a piece of the alkyl group and it has a phosphorylated group on it. If you give the antidote in the point where the alkyl group is added, there's no phosphorylation, there's no actual piece that's actually removed off of the alkyl group, then you can actually reverse the underlying toxicity. That's an important concept. All right, my friends, we talked about the basic kind of mechanism of action, all these different drug categories.
Now what we need to do is talk about what kind of conditions we utilize these drugs for. individually, and then we'll talk briefly about a cholinergic crisis as the adverse effect of these drugs. All right, guys, so let's now talk about the indications, the uses. Why do we actually give these particular drugs?
Now, there's not a ton of reasons other than what we'll talk about is myasthenia gravis, but there's a couple other ones that we could actually consider in certain conditions. So you know when a patient has very little GI motility, very little bladder contractility in situations, especially like post-operative. So generally whenever they have patients have decreased motility of the GIT and actually the bladder post-operative, we can actually give particular medications to increase the motility. So we can increase the motility of both of these particular organ systems in situations such as a post-op ileus. It also could be due to postpartum.
So you know postpartum? Whenever patients have postpartum urinary retention, that could be one particular reason. Or diabetes mellitus.
And in diabetes mellitus, this can actually cause gastroparesis or decreased types of nerve stimulation. So you can also see this particularly as what's called gastroparesis. So we may give these particular drugs.
And what are some of the drugs that we can give? One of them that I would actually want you guys to remember is what's called the bethanacol. So bethanacol would be one particular drug.
The other one that you could potentially consider here is fisostigmine, but we don't usually give this one just because it has a lot of CNS toxicity. So peridostigmine, neostigmine, maybe other doable options. I would say neostigmine would be the preferred agent just because it's a shorter acting, not as long acting.
And then the next one I would say is consider peridostigmine. Alright, so these would be the particular agents that we could give to potentially increase GI motility in situations of post-operative ileus, postpartum urinary retention, or some type of neuropathy in situations like gastroparesis in patients who have diabetes. Alright, the next other reason, this is actually an interesting one. So we can actually... We have that drug called methacholine.
And what methacholine does is it actually helps us in something called bronchial provocation tests. So what is it for? It's called bronchial provocation.
tests. And all that means is I have a patient who I'm concerned potentially has maybe asthma or some type of COPD or something like that, but particularly asthma. And patients who have asthma, normally their bronchial smooth muscle is super hyper responsive.
So it doesn't take much to cause these actual smooth muscles to go into an intense contraction. What does the actual drugs that are agonists of our parasympathetic, in other words, remember the vagus nerve caused bronchoconstriction? What are we going to do? We're going to increase the acetylcholine in those synapses on the smooth muscle and cause it to bronchoconstrict even more. So if I give methacholine to a patient who has asthma, what am I going to see?
I'm going to see an intense bronchospasm. And when it causes this bronchospasm, it'll cause their bronchospasm to drop their what's called forced expiratory volume. Okay, so it'll cause a bronchospasm that will decrease their forced expiratory volume in one second greater than 20%.
And that's a test that we can utilize in a diagnostic aid in situations like asthma. Okay? So these are two particular reasons.
Now let's come down and talk about things like glaucoma and secretions, particularly like from the eyes and from our actual oral secretion. Alright my friends, the next situation here is what if we have a patient who has something called glaucoma. So you know there's different types of glaucoma, there's open angle, there's narrow angle glaucoma, but the problem is that we're having an issue being able to drain the aqueous humor into these little channels here.
So you know you have these tiny little channels, I'll kind of just highlight it here in pink, it's called the canal of Schlem, and this little area, that's where you're kind of draining some of the aqueous humor. Now in situations of patients who have glaucoma, what we can do is we can actually help to change the pupil size. and the ciliaris muscle.
So what I can do is to help improve the drainage through this canal of shlem is I can help to pull the ciliaris this way. And if I pull the ciliaris this way, it opens up this angle here and improves drainage into the canal of shlem, which would help to decrease some of the pressure inside of this actual anterior chamber and posterior chamber. The second thing I can do is I can take the pupil, right? So the pupil is where the...
fluid such as the aqueous humor moves from what's called the posterior chamber into the anterior chamber. What if I did something, right, where I work to be able to help improve this actual angle? Now here's another particular reason. So you know here we have that canal of Schlemm, right? What if I take this pupil and what I'm going to do is I'm actually going to constrict it.
So this may seem interesting, right? But when I have what's called that acetylcholine working on these M3 receptors on the pupil, what will they do? They'll cause pupil constriction so it'll decrease the size of this pupil hole. Now this may seem odd like how is this going to help?
Let me explain how. What I can do is let's imagine here is my normal pupil and then right next to this is that drainage. All right, so here's that drainage.
This is normal, okay? If I have a patient who has pupillary, so let's say that this is actually going to be normal. What I'm going to do is, let me actually make this a little bit of a bigger pupil hole here. If I have them undergo pupillary dilation, you know what happens with pupillary dilation?
They're going to actually undergo a lot of dilation, and this space here is going to increase, and it's going to bunch up near this actual base. So then it's going to look like this. So it's going to look like this now. So it's bunched up so we have a larger pupil here, but look what we're going to be doing.
We're going to be kind of compressing here that actual canal of shlem. I'm going to be compressing it. And that's going to be altering the actual drainage of that actual... canal slim. Now what if I do, if I actually take and I actually constrict this pupil, so if I constrict this pupil, I'm going to narrow out my base.
If I narrow out my base now, look what that's going to do. It's going to improve and open up that canal slim and allow for better drainage through that, reducing the intraocular pressure. So in patients who have glaucoma, what I can do is, is I can cause one, the dilation. the pupil and that'll actually help to open up that canal of Shlem or the second thing is I can actually cause ciliaris contraction and that will pull this backwards so it'll pull this whole structure backwards more and help to be able to open up that actual angle. So these are great drugs that you can give in situations of patients who have what's called narrow angle glaucoma.
So that's one particular situation. We could also give, now what would be a drug that I could actually give here? I could give a drug called pilocarpine. So, pilocarpine, that would be one drug. You can also give another drug called carbacol, but we don't actually give this one anymore just because pilocarpine is superior and also carbacol has a lot of toxicity and side effects.
There's also some debate that actually physostigmine could also potentially could be used as well, but I wouldn't go too crazy down that one, but you can actually do a plus or minus as physostigmine according to the literature. But I would primarily focus on pilocarpine. Now, The other thing here that pilocarpine, carbacol also are actually decent at is that they also not only can actually cause contraction of the ciliares, pulling that angle, opening it up that angle, and allowing for better venous drainage into the canalis limb, or dilating the pupil, narrowing out their base, less compression of the canalis limb, but they also can act on those glands. So it can act on our lacrimal glands and increase lacrimation. So we can give these drugs and they can act on those actual muscarinic type three receptors and increase lacrimation and increase salivation.
And now why in the world would you want to do this? Two reasons. One is a patient has a disease that destroys these salivary glands and lacrimal glands. You know what that disease is called?
It's called Sjogren's syndrome. So it's an actual autoimmune disease. And we can give this particular drug to be able to help improve some of that actual salivation and lacrimation. especially if they have what's called carotid conjunctivitis zika. And so again, this would be particular reasons we would do that.
This is an autoimmune disease, right? So it's an autoimmune attack of those glands. The other one would be radiation induced.
So if someone had some type of radiation therapy and they actually caused some type of necrosis or fibrosis of some of the ducts and glandular tissue, it may actually reduce some of the secretion and drainage into the oral cavity or onto the actual eye. And so if we can actually help to improve some of that by giving these drugs, such as pilocarpine, carbacol, or physostigmy, I'm sorry, pilocarpine or carbacol, this will be able to improve salivation and lacrimation. So the two drugs that I want you to remember for lacrimation and salivation is going to be pilocarpine and carbacol.
All right, my friends. So that's going to be these types of indications. There's a couple more.
We're almost done. Let's kind of move on now to the next. big indication for these drugs and that's myasthenia gravis all right my friend so now what we got to talk about is actually the use of these drugs in myasthenia gravis so myasthenia gravis quick little recap on what that is it's a disease in which you have an autoimmune attack particularly where you make autoantibodies that are attacking the nicotinic receptors and they're blocking the nicotinic receptor ligand site so where acetylcholine is supposed to be able to bind and produce its type of muscle contraction effect it's being blocked by these nicotinic receptors and so the patients develop and inability to contract their muscle, which will cause weakness, right? So that's the key feature is that they'll develop what's called weakness.
And obviously, a very specific muscles, we're not going to go down that route. What you need to understand is that we can utilize particular drugs to improve weakness in these patients. And so what we actually would do is we can give a couple different drugs. One of the things I'm going to do is I want to talk about a couple different drugs.
And what they're going to do is they're all going to inhibit the acetylcholinesterase. And what we know about this drug is that acetylcholine esterase will take and do what? It's supposed to be able to take acetylcholine, so here's our acetylcholine that's in the synapse here. It's supposed to take and convert it into choline, into a small acetyl group, and then be reutilized, right? But it renders acetylcholine inactive, okay?
If I inhibit this enzyme, I prevent this type of process. And I decrease the actual breakdown of acetylcholine. If I do that, I start increasing, increasing, increasing, increasing, increasing acetylcholine in the synapse. So much so that it actually starts competing with the antibodies and knocking these antibodies out of that actual site. And if I start beating some of the antibodies out of that site, then acetylcholine will potentially be able to bind to these actual receptors.
Maybe some of them still will be bound to the actual nicotinic antibody. But maybe some of the acetylcholine will be able to beat that receptor, beat that antibody out of that actual receptor site. And that's an important thing because then what we can do is we can have an improvement in ion influx into this portion here and maybe have some type of a contraction that decreases the weakness.
All right, that's the whole goal. Now, what kind of drugs could I actually do? Well, they obviously have to be acetylcholinesterase. None of these are going to be any direct type of like nicotinic agonists. Okay, they're not going to be good enough in these situations.
So we need to be able to increase the acetylcholine to high levels. Now, there's a couple different drugs here. The first one is not used to treat. So again, what is this disease here called?
Let's actually write this down. This is actually... They're going to be used in what's called myasthenia gravis and it's again it's an autoimmune disease where antibodies attack the nicotinic receptors block acetylcholine preventing them from being able to contract they develop weakness. If we give acetylcholine esterase inhibitors they'll increase the acetylcholine and beat the nicotinic receptor antibodies out of that site and still be able to bind and produce some type of stimulation to the muscle reducing the weakness.
The drugs I could give, first one, is called edrophonium. Now, edrophonium is not going to be used to treat. It is not used to treat myasthenia gravis.
It can be used to help diagnose. Myasthenia gravis. And we call this test, where we give edrophonium and help us to see if there is a possibility, we call this what's called the tensilon test. And it's actually a really cool test.
So, edrophonium is a very short-acting drug. Like, honestly, you might get about a minute or two out of this drug. So if you have a question, if a patient has myasthenia gravis, they're really weak. Let's say that they're not able to move their arms up very much.
They're very, very weak in their arms. You give them edrophonium. Edrophonium is a drug Hedrofonium inhibits this particular enzyme.
Increases the acetylcholine in the synapses for about a minute or two. Knocks some of these actual antibodies out of the ligand site. You stimulate those receptors. You should see an improvement in their weakness.
And it's very short-lived. And so that would be one of the things that we could utilize in helping us to aid in the diagnosis of myasthenia gravis. Obviously, that's not the most important test. Obviously, we have to check the antibodies.
But it helps us in the diagnosis. That's one cool drug. The next one that we should talk about here is we have the other drugs called fisostigmine, pyridostigmine, and neostigmine.
Now, with these, neostigmine is really good in the treatment of myasthenia gravis. But when we talk about time, it's not as long-lasting as compared to pyridostigmine. So when you compare the duration, let's actually put duration of action.
duration of action. In comparison between neostigmine and peridostigmine, it is significantly less than compared to peridostigmine. Peridostigmine is a lot longer lasting, so it's better in the chronic management of patients with myasthenia gravis.
So when we talk about these peridostigmine, I would want you guys to remember that pyridostigmine is a longer duration. But either way, I could pick between these, neostigmine and pyridostigmine, either one of them are utilized in the treatment of myasthenia gravis. more likely chronic long-term management would be better managed with peridostigmine because I'm going to get about six hours out of that drug in comparison to neostigmine I might not get any more than about three hours out of that drug so it's an important concept to understand The last one that's actually a part of this group of the you know reversible inhibitors is the what's that one the physostigmine.
We don't utilize this drug and the reason why is we don't so stay away from no physo and the reason why is because this one has CNS toxicity. So because it's very lipid soluble we do not want to give this one to treat myasthenia gravis because it'll cause excess excessive excitation of the central nervous system leading to seizures, convulsions. And so that's an important concept to understand.
So that's why whenever we utilize these drugs, edufonium is used in aiding in the diagnosis via the Tensilon test. Tensilon and the neostigmine and peridostigmine can be used in myasthenia gravis, but peridostigmine is probably going to be the preferred agent just because it has a longer duration of action and it's going to be better in the chronic management of myasthenia gravis. Okay, I hope that made sense. Now, one more really cool thing about edrophonium. Let's say that you have a patient who has myasthenia gravis.
And what we're trying to figure out is they come to the office and they say, hey, doc, man, I'm getting more weak than usual. I'm even more weak and I'm taking my medication. I'm taking my piretastigmine. I don't know what's going on.
So they have myasthenia gravis. And what you're trying to figure out is, okay, do they have what's called a myasthenic... Crisis. Meaning that their disease is getting worse.
In other words, in myasthenia crisis, they're having more antibody attack of their nicotinic receptors. And you're giving them pyridostigmine, right, to try to be able to increase their acetylcholine, but it's not enough. Their crisis is worse than the actual dosage of pyridostigmine that you're giving them.
In other words, they need more pyridostigmine. So you're giving them a drug to be able to inhibit the acetylcholine esterase to increase the acetylcholine, but they're just having such an intense attack. autoimmune attack right now that they're having a big exacerbation that the dose of the actual peridostigmine is not enough to increase the acetylcholine to displace the receptors.
So they're having an exacerbation of their underlying myosinia gravis. The other question that you have to say is, is this a cholinergic crisis? This is where it can be somewhat kind of confusing initially. So a cholinergic crisis.
In other words, am I giving them too much of the peridostigmine? What does that mean? Maybe I have these acetylcholine binding onto these receptors very powerfully, and I've given a dose of predastigmine, and it is really, really inhibiting this particular enzyme, where the acetylcholine levels...
are through the stinking roof. And they are causing so much stimulation of this muscle that the excessive stimulation, too much of one thing is always not a good thing, that too much excessive stimulation of the muscle will lead to weakness. So in this situation, the weakness that they were having was because they weren't getting any types of ions into this actual muscle cell.
And so that was because of their myasthenia. They were having so much blockage of those. receptors that they weren't getting any ions into their actual muscle cell.
And that was because of the disease getting worse and not a high enough dose of predestigmine. In this situation, you give them too much of the predestigmine, increase their acetylcholine, cause their muscles to be overstimulated and induce weakness. You don't know which one it is.
What you could do is just say, in this situation, I would do what? I would increase the dose of my predestigmine, send them home and see if they get better. Or I would decrease the dose of the predestigmine, send them home, see if they get better.
But that's a scary situation to do. What if I had a drug that I I could give that would only last about one to two minutes, it would give me the answer and then I could send them home with somewhat of confidence knowing that I've given them the right answer to their situation. That's where edrophonium comes into play. If I give them edrophonium, so imagine here, let's actually say I give them edrophonium and the situation. If I give them edrophonium, what it's going to do is it's going to work to inhibit this enzyme even more.
If I inhibit this enzyme even more, what am I going to do to my acetylcholine levels? I'm going to increase my acetylcholine. levels.
I'm going to knock some of these antibodies out of the site and then I'm going to allow for acetylcholine to bind to some of these actual sites and then that's going to increase ion influx. And the ion influx that I'm going to allow for is going to cause more positive ions, leading to contraction of the muscle and decrease the weakness. So in a myasthenic crisis, if I give them edrophonium, it'll actually decrease their weakness. It'll improve their weakness.
They'll get stronger. And then I know, okay, that's the answer then. They're in a myasthenic crisis. What's the answer? Increase peridostigmine.
Send them home with that. cholinergic crisis, I give them adrofonium. I'm going to inhibit this enzyme even more. I'm going to increase my acetylcholine levels even more. And then because of that, I'm going to have more positive ions coming into the cell and I'm going to increase my weakness.
I would know right then and there if they have a worsening weakness or they have other cholinergic signs like diarrhea, urination, they have excessive salivation, lacrimation, they have bradycardia, excessive kinds of cholinergic cholinergic crises types of findings, I would be able to tell, ooh, do not increase the dose of their peridostigmine. I would see an increase in their weakness with this, and I would say this is likely a cholinergic crisis. We have to hold some doses of peridostigmine, and then from the future, we need to decrease the peridostigmine doses. I hope that makes sense.
The last thing that I want to talk about here with a couple other situations, and we'll talk about the central nervous system drugs for cholinergic agonists, is we can also utilize these drugs in somewhat of a way of overdoses. So imagine a patient is taking in... anticholinergic.
So they're taking a drug like an anticholinergic. What are some anticholinergics? Well, we're going to have that eventually in another video, but a couple of them that are really important are things like tricyclic antidepressants, atropine, things of that nature.
And what these are potentially trying to do is that these are trying to decrease the acetylcholine levels. And so what you can do is because these drugs are potentially acting at these you know nicotinic receptor sites or other types of sites what you can do is you can give them a very particular drug that would be able to get rid of or get the actual drug out of that potential site and reverse the actual toxicity of the TCAs or atropine. So if someone had an overdose of these particular drugs, what could I give to be able to displace them out of these sites that the way they're not causing this anticholinergic toxic effect?
I could give them a particular drug called Fisostigmine. So Fisostigmine would be a decent drug to be able to give in situations such as anticholinergic overdose, such as TCAs or atropine or even like atypical antipsychotics. The other situation is if I have what's called a neuromuscular blocker.
So if I have a drug called a neuromuscular blocking agent. So I had someone who actually had to get paralyzed because they were getting intubated. They were performing a surgical procedure and they needed to be held still.
In that situation, the neuromuscular blocking agent is binding onto these nicotinic receptors and inhibiting these nicotinic receptors from being being able to contract because we don't want the patient to move as we're cutting into them or doing some type of procedure. Afterwards, when they're in the recovery unit and they're still not moving and you need to get them to move, what we can do is we can reverse the effect of the neuromuscular blocking agent if we gave too much of it. And we can give a drug that actually can competitively, and this is what's really interesting, it can competitively act here and knock that actual drug out of the site.
And that's where neostigmine can actually come in. So neostigmine is one of those interesting ones where neostigmine has the ability to act a little bit like a nicotinic agonist in a way. way and an acetylcholinesterase inhibitor. So it can act as an indirect agonist and in some small degree even a direct agonist. If you give this neostigmine it would be able to knock this neuromuscular blocking agent out of that site and then allow for the contraction of the muscle to reverse the actual paralytic effect.
So if you're trying to reverse a neuromuscular blocking agent you can give something called neostigmine. And if you're trying to treat or give an antidote as an overdose to tricyclic antidepressants or atropine, you can give fisostigmine. All right, the next thing we have to talk about is some of the things with Alzheimer's disease.
All right, my friends, so the other thing I told you is that there's actually, again, cholinergic pathways within the central nervous system. There's a really interesting nucleus. It's called the nucleus.
of Maynard. And what this nucleus does is it has these cholinergic fibers that actually go up to the central, like up to your cortex and provide cortical stimulation. And this is important within our cognitive function, right?
So our memory, etc. What happens is that in patients who have a disease called Alzheimer's, they have a lot of different types of And they start developing something like dementia or a decrease in their cognitive function. What happens is because this pathway is releasing acetylcholine, there's a reduction in the acetylcholine within these pathways. And because there's a reduction in the acetylcholine, there's a reduction in the acetylcholine. in the acetylcholine, this causes a reduction in cognitive function.
And what we can do is we can give particular drugs to work to actually increase the acetylcholine in the synapses to hopefully improve the actual cognitive function, improve quality of life in patients with Alzheimer's. And that's where we would give particular drugs such as, we would give denepazil. We would give something like Rilastigmine.
And the other one that we didn't have written down over there, but I'll actually mention it now, called Galantamine. Now, the nice thing about these drugs is that they're tertiary amines, so they can penetrate into the actual central nervous system across the blood-brain barrier. But these will work to be able to do what?
Inhibit the acetylcholine esterase. If they inhibit the acetylcholine esterase, what will they do to the actual acetylcholine levels? They'll work to increase your acetylcholine levels, which will work to improve cognitive function. and memory. It does not stop the progression of Alzheimer's.
It does not necessarily completely cure them of Alzheimer's. All it does is, is it slows the progression of Alzheimer's and hopefully helps to improve their quality of life. So it just slows the progression. of the disease.
It does not stop it. It does not cure them in any way, shape, or form. It's important to remember that. The last thing that we have to talk about here, there's lots of adverse effects of these drugs, and some of them are not as severe as what we're going to talk about now.
but I think it's really important whenever you guys get an exam and they're asking you about a particular drug such as one of these and they start to have these particular types of effects. Are they in a cholinergic crisis or not? And so this is actually really easy to understand.
And you want to know why? It's because we have a strong understanding of our cholinergic system now. And so if a patient has a cholinergic crisis, it's going everything that we talked about on the complete opposite end of the board, we're going to ramp it up.
Their pupils, they'll have increasing meiosis. Their pupils will be like pinpoint. They'll have increased lacrimation. Alright, so they'll be kind of, their eyeballs will be watering like crazy. They'll be salivating.
They'll have just drool coming out of their mouth. So massive salivation. They'll have an intense drop in the heart because it's actually on the M2 receptors.
And then subsequently a drop in their cardiac output that may cause hypotension, drop in their blood pressure. They may also have intense bronchospasm where they have... difficulty being able to breathe and wheezing.
They may also have increased GI motility. And so because they're just having tons of GI motility, they're just shooting, you know, chocolate rain is flooding from their Hershey highway. So they're having increased defecation and diarrhea. They're causing contraction of their bladder and just shooting urine out like it's going out of style.
So there'll be increased urination. And then on top of that, they're going to have excessive stimulation of our skeletal muscles. And if you excessively stimulate the skeletal muscles too much, what will actually this do?
This will cause weakness, right? So this may lead to weakness. And then on top of that, like I told you, because some of these drugs can actually cause excessive stimulation of the central nervous system, if you excite it too much, it can cause agitation.
It can cause restlessness. It can cause tremors. But what's the most concerning thing? It can cause convulsions.
So increasing the activity of the actual neurons can potentially lead to convulsions. So if I give one of these types of agonists, one of these cholinergic agonists, and I maybe just give a little bit too much of that, these are all of the effects that I could see. But there's one more. Remember I talked about the sympathetic nervous system? It was actually from the thoracolumbar output, but the cholinergic system was a part of that.
Remember, the preganglionic releases acetylcholine. The postganglionic, where that sympathetic neuron releases acetylcholine, act on the M3 receptors on the sweat glands and caused increased sweating. So these are the big things to think about. And you know what? Actually, a very intelligent person came up with a mnemonic to be able to remember these.
And the mnemonic is, the mnemonic to remember this is dumbbells. So you can kind of just look at it, but diarrhea. So excessive diarrhea, excessive urination.
In this case, they would actually have intense pupillary constriction like meiosis. They would also have bradycardia. They would have bronchospasm. They would also have excessive excitation of their muscles and central nervous system, which can cause weakness and convulsions.
They can also have lacrimation. They can have salivation and sweating. So this is one of the potential ways to be able to remember this type of cholinergic crisis.
Now the question that also may come up is, what kind of drug can I give to reverse the actual cholinergic effects? In this situation, I want to give an anticholinergic agent. And so there's two particular drugs I can utilize to reverse or give as an antidote. One is atropine. And the other one that I can actually give is called pralidoxine.
Okay, pralidoxine. But again, don't forget this, guys. Remember I told you that you can give pralidoxine to a patient who takes an irreversible indirect agonist, like one of those nerve agents or pesticide agents or organophosphates or the ecothiophate.
We can give it, but we have to give it to a patient who takes it. have to give it before what occurs aging where the alkyl group piece of it gets removed off all right we've talked a ton about cholinergic agonists i hope it made sense and i hope that you guys enjoyed it we're not done though let's do a quick couple of questions and see if you guys understand all this stuff all right Let's do some questions here. Let's put our minds to the test. Let's see if you guys understand the cholinergic agonist.
So question number one, botulinum toxin blocks the release of acetylcholine from the cholinergic nerve terminals. What is a possible effect of Botox? Well, think about what acetylcholine does at the actual nerve terminals on a muscle. So acetylcholine is supposed to be able to trigger the muscle to be able to contract. Alright, so if there is an absence of acetylcholine because you're blocking its ability to be released, what do you think is going to be the overall effect?
Are you going to be able to cause skeletal muscle contraction? No. So there's going to be an absence of skeletal muscle contraction.
What's the opposite of the contraction? Paralysis. So this should lead to skeletal muscle paralysis.
And that's one of the effects of the botulinum toxin. So it should be skeletal muscle paralysis in this situation. Alright, beautiful.
Next situation here is we have a patient who develops urinary retention after an abdominal surgery. So they like a post-op urinary retention and obstruction was completely ruled out as a cause for their retention. Which strategy would be helpful in promoting urination?
We have to remember, again, there's different types of receptors. In this case, the bladder is what's called a smooth muscle. And so we think about smooth muscle. We know that there is specific types of receptors. So there's nicotinic receptors and muscarinic receptors.
Nicotinic are present on the pregang, on the... cell bodies or dendrites of the postganglionic motor neurons. And they're also present on the smooth muscle, cardiac muscle, and glands of target organs. I'm sorry. I apologize.
The nicotinic receptors are present only on the dendrites and cell bodies of the postganglionic motor neurons and on skeletal muscles. Apologize for that. Muscarinic receptors are found only on smooth muscle, cardiac muscle, and glands of target organs.
Let me say that one more time. Nicotinic receptors are found in the dendrites and cell bodies of the postganglionic motor neurons. on the skeletal muscles. Muscarinic are present on smooth muscle, cardiac muscle, and glands.
Now when we talk about that, we know that the bladder is a smooth muscle. Now the question is, which type of muscarinic receptor is it? Remember I told you that there's a bunch of different types, but there was two main ones that I wanted you to remember. M2 was the inhibitory receptor, and you could also, if you wanted to, remember M4.
M3 was the primary stimulatory receptor. And if you really wanted to remember M1, M3, M5 would also be stimulatory. But if that's the case, then we have M3 receptors here present on the smooth muscle of the bladder. So that's going to want to promote contraction. So if we have acetylcholine, it'll bind onto the M3 receptor and produce contraction.
That's important. So look at the question. Would we want to activate nicotinic receptors? No, because that's not present on smooth muscle. It's only on the postganglionic.
motor neurons, their dendrites or cell bodies, or skeletal muscle. Do we want to inhibit the release of acetylcholine? No, I actually want acetylcholine to stimulate these M3 receptors.
Do I want to inhibit the cholinesterase enzyme? If I inhibit the cholinesterase enzyme, that'll increase the acetylcholine in the synapses, and that'll actually have it stimulate the M3 receptor more. That would be the correct answer.
And do I want to block the muscarinic receptors? No, I want to actually stimulate them. So it has to be C, inhibit the choline esterase enzyme, because that'll help to prevent the breakdown of acetylcholine, increase the acetylcholine in the synapse, and have it stimulate the M3 receptors and cause smooth muscle contraction.
Should be C. All right, three, which of the following drugs could theoretically improve asthma symptoms? Well, you have to think about this.
All of the receptors on the smooth muscle of the bronchioles is going to be M3 receptors. So whenever any kind of cholinergic agonist binds onto it, It's going to cause bronchoconstriction to some degree. Bethanacol, that is one of those types of muscarinic agonists. Pylocarpine, muscarinic agonist.
Pyridostigmine, it's a muscarinic. It's actually going to increase the acetylcholine levels in the synapse to bind to muscarinic receptors. And so these three are all going to cause bronchoconstriction.
Atropine is the one that we did not mention. And guess what? Atropine is an anticholinergic. So it's going to... oppose the normal muscarinic function.
So in other words, all three of these are going to cause bronchoconstriction. Atropine is the exact opposite. When it binds onto the muscarinic receptors, it inhibits them and prevents bronchoconstriction, thereby causing bronchodilation.
So the answer should be atropine. If an ophthalmologist wants to dilate the pupils for an eye exam, which drug class of drugs is theoretically useful in this situation? Well, think about it. What kind of muscarinic receptors are present?
on the actual muscle of the pupils. Well, remember, this is going to be muscarinic 3 receptors. And normally, what does the parasympathetic do?
It causes pupillary constriction. So, if I stimulate the muscarinic receptors, the M3 receptors of the pupil, they're going to constrict. So, think about that then. Would I want to cause an agonist to bind onto that muscarinic receptor to cause it to dilate? No.
Because if I stimulate the muscarinic receptors, agonist that's going to cause pupil constriction. Do I give an inhibitor, an antagonist? Yes.
Because if I block the muscarinic three receptors, they will not constrict and therefore subsequently dilate. Just to continue though, pilocarpine, this is a agonist. So it's an actual cholinergic agonist, specifically a muscarinic.
Neostigmine, this is a cholinesterase inhibitor. So it's going to increase acetylcholine and that'll stimulate the muscarinic receptors. So pilocarpine, neostigmine.
And some muscarinic agonists, these are all kind of synonymous to one another. So we want the antagonist to cause pupillary dilation. In Alzheimer's disease, there is a deficiency of cholinergic neuronal function in the brain.
Theoretically, which strategy is useful in treating symptoms of Alzheimer's? Okay, think about it. In Alzheimer's, there is decreased acetylcholine then. All right, there's decreased acetylcholine in the synapses.
If I give a drug that increases the acetylcholine in the synapses in the brain, that would potentially be a beneficial situation. So which one of those would give me that answer? Inhibiting the cholinergic receptors in the brain. No, that would make it even worse.
Okay. Because if I inhibit the cholinergic receptors, acetylcholine won't be able to even bind and produce its effect for cognitive function and memory. Inhibiting the release of acetylcholine.
That's again, going to make it even worse because then I have no acetylcholine in the synapses. I'm trying to increase acetylcholine and its effect. Inhibiting the acetylcholine anhydrase enzyme in the brain. Oh, that'd actually be a good idea because if I inhibit acetylcholine esterase, I prevent the breakdown of acetylcholine and therefore I maintain acetylcholine levels in the synapse to stimulate this actual neuron and therefore improve the cognitive function and memory. patients with Alzheimer's.
So it has to be C, but let's keep going. Activating the acetylcholine esterase enzyme. No, that would be worse because again, I'd be breaking down acetylcholine, decreasing acetylcholine in the synapses. So B and D are pretty much saying the same thing.
And then A is saying, well, if we have acetylcholine, even if it's present, it's not going to work at the receptor. That's again, the same concept. Overall, it's producing less effect of acetylcholine or having less acetylcholine in the synapse.
So we want lots of acetylcholine in the synapse. So it has to be C. Alright, cholinergic crisis. An elderly female who lives in a farmhouse was brought to the emergency department in a serious condition after ingesting a liquid from an unlabeled bottle found near her bed, apparently in a suicide attempt.
She presented with diarrhea, urination, convulsions, breathing difficulties, constricted pupils, and excessive salivation. So remember the mnemonic that we talked about was dumbbells. So diarrhea, urination, they're going to have also meiosis, so they'll have the pupillary constriction. Then they'll have bronchospasm, so breathing difficulties.
They'll have excessive excitation of their CNS and their skeletal muscles, so convulsions and potential weakness. And then they'll have lacrimation and they'll also have salivation. And then again, in this situation here, you can obviously see that they're going to have lots of salivation.
And they would also have lacrimation as well. And sweating. If they had sweating in here, they don't mention that. But either way, this is a cholinergic crisis. Most of the symptoms that's present there is definitely a cholinergic crisis.
So, okay, which of the following is correct regarding this patient? They consumed an organophosphate pesticide. Remember I told you organophosphates are those ones that cause irreversible inhibition of the acetylcholine esterase enzyme. If you irreversibly inhibit the acetylcholine esterase enzyme, You make the acetylcholine levels within the synapses stay elevated for a long period of time.
And if you don't catch it before they go into what's called aging, it's not reversible. You can't give them an antidote. So it is likely that this patient does have organophosphate poisoning. And that is likely the cause. That it was some type of cholinergic agonist, like an organophosphate, an irreversible acetylcholine esterase inhibitor that caused this.
The symptoms are consistent with sympathetic? No. A sympathetic would not produce these types of effects. Again, sympathetic would not produce these parasympathetic effects.
Her symptoms can be treated using an anti-cholinesterase agent. Oh my gosh, you killed him. So if you give them an anti-cholinesterase, you're going to increase their acetylcholine levels in the synapse even more.
So you'll worsen all this stuff. Her symptoms can be treated with a cholinergic agonist. Okay, you want to put her into the ground a little bit quicker?
Sure, give her that. But that's not going to benefit her. It's going to, again, worsen her actual cholinergic crisis. So it can't be C, can't be D, because you will absolutely murder them. And B just is not going to be the effect.
Sympathetic doesn't cause any of these types of effects. So it's likely A. All right.
Patient has received a neuromuscular blocking agent for skeletal muscle relaxation during their surgical procedures, is experiencing some mild skeletal paralysis, muscle paralysis after surgery. Which one of these drugs can reverse the effect of the neuromuscular block? Remember, there's one that was an antidote or reversal of...
TCA, tricyclic antidepressants, atropine, and antipsychotics, and that was physostigmine. The one that reverses the neuromuscular blockers because it has somewhat of effect on the nicotinic receptors, it can push the neuromuscular blocker out of that site and bind onto it would be neostigmine. All right, great. 60-year-old female has a cancerous growth in the neck region underwent radiation therapy. Her salivary secretions have been reduced due to the radiation she suffers from xerostomia dry mouth.
Which drug is most useful in treating xerostomia? We don't use acetylcholine anymore. And atropine is an anticholinergic agent. So we're talking about cholinergic agents. Anticholinergic means that you're going against parasympathetic.
Remember, parasympathetic, you want to cause salivation, lacrimation, and those types of effects. So atropine would oppose that. So it can't be this one.
Acetylcholine would be a good answer, but we just don't use this drug ever. And that comes down to pilocarpine and ecothiophate. Do you remember what ecothiophate was? Ecothiophate is...
is actually going to be one of those irreversible anticholinesterases. We do not want to use this. It's going to have some nasty side effects.
And so we try to never use this drug. And therefore, the last one that would be remaining is pilocarpine. So pilocarpine would be a potential drug. And then the other one is carbacol, but we don't use that one because it also has lots of side effects.
That would treat things like this situation, glaucoma. And also helping to be able to improve lacrimation and salivation in patients who have Sjogren's syndrome or radiation-induced decreased salivary and lacrimation. So pilocarpine should be the answer. 40-year-old male presents to the family physician with drooping eyelids, difficulty chewing and swallowing, and just general muscle fatigue.
even on mild exertion. Which agent could be used to diagnose myasthenia gravis right then and there in this patient? So obviously we send off acetylcholine esterase, the acetylcholine, the nicotinic receptor antibody.
So that's obviously the diagnostic test. But we can give them a very specific drug that's very short acting, lasts like maybe one to two minutes. And what it's going to do is it's going to inhibit the acetylcholine esterase enzyme and increase the acetylcholines transiently for a couple minutes. In the synapses to stimulate the skeletal muscles and give them more contraction and improve strength for that small time period. What was that drug that I told you that we utilize as kind of a little diagnostic measure called the tensilon test?
It's edrophonium. Edrophonium was the answer for that one. Good. All right. Last question here is atropine.
It comes from this plant called Atropa baladana and it's a muscarinic. antagonist, right? So it's an anticholinergic. Which of the following drugs or classes of drugs will be most useful in treating poisonings due to atropine?
Remember I told you that neuromuscular blockers are going to be pushed out by neostigmine. Which drug pushes out tricyclic antidepressants, pushes out atropine, pushes out antipsychotics? Fisostigmine. So it should be fisostigmine. All right, Ninjers.
So that covers all the questions and that covers this video on our... cholinergic agonist. I really hope it made sense.
I hope that you guys did enjoy it and learned a lot. Love you. Thank you. And as always, until next time.