Parkinson's Disease Drugs

What's up, ninja nerds? In this video today we are going to talk about Parkinson's medications or pharmacology and Parkinson's

disease

. There is a lot to discuss before we begin. If you guys really benefit from this video, it will really help you understand some things. after this please support us and the best way to do so is by hitting the like button by commenting in the comment section. Most importantly, subscribe in the description box too. We have links to our website. We are there. We have some. Stunning illustrations, some great notes to follow during this process, so check it out.

Well, let's start talking about these medications, so I think the first thing we need to do before we can really understand the different names of the medications. and the mechanism of action and some of the adverse effects in the classical way that you should talk about pharmacology, we really need to have a good understanding of the basic pathophysiology of the anatomy, some of the pathways that are involved within the circuits involved in Parkinson's

disease

before. We can really go over the mechanism of action, so let's do it briefly. I don't want to waste a lot of time, so I want to go over this relatively quickly.

If you want more details on this, watch our video on basal ganglia where we go over all the anatomy, all the circuits and many more details, we are going to go at a little faster pace to build our base, so when we talk about the anatomy of the basal ganglia here we have abbreviated Bg, there are a couple of different structures, one of the first ones that I want you to remember here that I'm going to color here in this pink color is called the caudate nucleus. Okay, this is called the caudate nucleus. Now there are a couple. other gray matter structures that are situated deep within the cerebral cortex, so here in this area like the diencephalon, we have another structure that I'm going to draw here in this orange color, so let's do it in orange, this is actually going to be the lentiform nucleus and there are three components this component here will be called putamen this here the two components are called globus pallidus there are two parts the external globus pallidus which will be this component here and the globus pallidus in turn so again let's remember what these structures are here again we are going to have all this is the lenticular nucleus and it is formed by the putamen external globus politus internal globus pellitus well, very good, another particular structure, let's draw this one in blue it will be these egg-shaped structures that are located here in the center and they will be called the thalamus, so each one is a thalamus, so we have the caudate nucleus, we have the lenticular nucleus and we have the thalamus and again the lentiform is the putamen globus extended its externus and internis very well a couple more structures almost there The next one is there is a structure just below the thalamus that we are going to draw this is like this picture just below the thalamus this is called the subthalamus so the subthalamic nuclei are also involved in the structure and there is one more and super critical to understanding Parkinson's disease in the midbrain, so here we are in the midbrain, there are these structures here that we're going to highlight here in black. the substance the substance niagara well, now in Parkinson's disease there is destruction of the neurons within the substance, which causes a decrease in dopamine.

We'll go over all of that, but again we'll add other terminology, so we have the lenticular caudate, which is the silvery putamen globus. sexual terrorist internist thalamus subthalamus and substance a couple more terminologies, one is that when we take the caudate and the putamen we actually have a particular name for that and you want to know that it's called the striatum, okay, it's called the striatum and the reason why which I want you to know that these two particular structures that connect the caudate and the putamen, called the striatum, are the dopaminergic neurons that we are going to review, which connect to this striatum and every time there is destruction of the neurons in the substance , the entry of dopamine into the striatum is altered and that is where you will really see destructive processes in Parkinson's disease.

This pathway is called the nigro-schreidel pathway, which is one of the big pathways that is actually altered in patients who have Parkinson's disease. Well, we have the anatomy below. The next thing we need to do is take this structure here and just zoom it in, so here's our cortex, here's the hairy form with the putamen globus plate, the internal external thalamus and then this is going to be the substance, so this I'm going to put something substantial there and then we will have another pathway, so there are two pathways involved here, one is called the direct pathway and the other is called the indirect pathway, but again we have the cortex, the putamen with the the unfortunate core formed by fluff with the plate putamen globus is the internal external thalamus, this is the subthalamus and again we have our substance.

Now you're probably wondering why there are two pathways again if you haven't seen our video on the basal ganglia. I'm going to talk briefly about this here, the direct path is the design path to help play a role within the motor movement, particularly desired motor movements, if I want to be able to grasp this, if I really want to be able to use this particular marker and perform a particular movement has to be smooth, they have to be able to start it, stop it, all those types of fine tuning events are modulated or altered through the direct pathway now, if I also want to avoid any unwanted motor movement, like when I bring my pen or my marker on the board by hitting it on the board which will actually be modulated through the indirect pathway, so the basic concept is that the direct pathway wants to help initiate the motor movements and perform the desired motor movements, whereas the indirect route is more those trying to prevent unwanted motor movements, in other words, if I want to flex here at my elbow, I want the biceps muscles to really contract and work.

I don't want my triceps muscles to contract, I want them to relax, which I can allow. that movement occurs, so it's that kind of concept now the basics of this pathway are really important from the actual cortex, we have particular neurons, these cortical neurons and they're actually carrying the glutamate to this area of ​​the putamen as well as what else . the caudate nucleus I got rid of the caudate so I'm just going to represent the putamen but that represents the striatum these neurons from the cortex will go down and release glutamate in particular neurons located within the striatum there will also be some neurons located here in the striatum and they will What happens is that these neurons will actually extend from the putamen up here to the globus pallidus internus.

Now, when the rind is released, I want you to remember that the red will represent the glutamate. Well, glutamate is a stimulating neurotransmitter blue is going to represent gaba gaba is an inhibitory neurotransmitter okay, when the actual cortical neurons want to generate a movement, so let's say my cortex, my motor cortex is like, hey, I want you to move. the arm, I have to consult my basal ganglia, let them know, say: hello basal ganglia, this is the motor movement I want to perform. Can you make sure it's smooth? It's nice, it's not going to be pretty.

You know, I have a good motor movement that I want to perform and then avoid any unwanted motor movements. movements yeah, I got you, this is how I'm going to do it, send that information to the puten and then what does it do? It releases glutamate in this particular neuron. What I say, glutamate does what it stimulates, so it will stimulate this particular neuron. neuron located in the putamen now from this neuron it will extend from the putamen or from the striatum to the globus pellitus and the turn and what is it going to release in the neuron located right here is it going to release gaba now if I stimulated this neuron, it will fire when it fires, it increases action potentials along its neuron and releases a large amount of gaba into this neuron.

Now this neuron is located in the globus plate as internal and extends from there to the thalamus, but this is what I want. to understand this neuron releases glutamate stimulated this one is now stimulated he sends action potentials and releases gaba gaba does what it inhibits so what would be the real effect here would it inhibit this particular neuron from activating well so this neuron does not fire now. What color is? Think about it. Is blue. So what does gaba release? If it is inhibited, will it release gaba? No, therefore, it will be able to inhibit this particular neuron.

No, now this neuron is released from inhibition and this neuron. and the thalamus guesses what color it is, it's red, then it will release glutamate and send it back to the actual cortex and it will release glutamate here in the cortex to simulate these glutaminergic neurons, then they will go out to the particular skeletal muscle and trigger that skeletal muscle to Initiating a contraction, so this is the direct pathway from the cortex to the striatum actually stimulates those GABAergic neurons, they are stimulated, they release GABA, they inhibit the neurons in the political globe and the turn, if they are inhibited, they do not release GABA if you don't release gaba you don't release an inhibitory neurotransmitter, so you release these thylamic neurons from inhibition and you stimulate them, then they release glutamate into the cortical neurons and initiate a motor movement, that's how this works now, how does the substance get in?

This is very simple, the substance has particular neurons that extend here to these neurons and the putimen is in the striatum and it releases dopamine, but the dopamine that releases it is in a particular receptor here and I'm going to put it aside here, but this receptor is called the d1 receptor now, whenever dopamine reaches the d1 receptors, it stimulates them, it works so we can call it g stimulatory protein, so it increases the cyclic amp protein kinases and then it causes a cationic reflux influx. I'm sorry and if that's the case, what would I do to this neuron?

I would stimulate her like a son of a bitch. Now this nerve let's make it stimulating here so you can see it, so it will release a lot of dopamine in these d1. The receptors stimulate this neuron if you stimulate it in addition to the third glutamate stimulation, you will have a great stimulation of this neuron. Now it will hardly release gaba. If it releases almost no gaba, that will do it again. Sorry, if you stimulate this neuron, it will release a ton of gaba. I apologize, if you really stimulate this neuron, it will release a lot of gaba, which will inhibit this neuron a lot.

Now this neuron is super inhibited, it won't release gaba if it doesn't release gaba, you will intensely release this thalmic neuron from inhibition and it will fire like a son of a gun, it will send action potentials to the cortex, it will stimulate those cortical neurons to go away. and they actually stimulate movement very intensely, so what you're seeing here outside of the nigrostrial pathway is what you're noticing, one thing in particular which is actually doing it here in orange, you're noticing that this will increase motor movement, that's all. concept here you are increasing the motor movement now, what would I do with the indirect pathway very quickly here you have again cortical neurons the same that come from the cortex and are bringing these neurons to the putamen or the striatum?

Again, that's the caudate nucleus and the putamen releases glutamate into these particular neurons. Remember that glutamate does what it stimulates in particular, it is a stimulatory neurotransmitter, so it acts on the same neurons located here in the putamen or the striatum. Here's the difference, although in the directive they said all the way to the inner pale globe we're going to go in, we're going to take a little detour if you want, so now what I'm going to do is take this nern just go here to the political globe external and if I'm releasing glutamate into this neuron, what will it do to that neuron?

It will stimulate it, so I'm going to stimulate this particular neuron, it will fire, it will release. gaba, what is gaba doing? So if I release a ton of gaba, what will it do to this particular neuron? It will inhibit it. Where does this neuron go to the subthalamus? Now this will go down to the subthalamic nucleus in the subthalamic nucleus we have what color here we have these red neurons and guess where they go, they go up here to the politus globe and turn us so you can see how we are going to get back on this path here we just made a little detour towards the subthalamus let's continue here it releases glutamate in this neuron there is glutamate released under this iron and it is actually stimulated it releases gaba it inhibits this neuron if this neuron is inhibited it can release gaba no if it can't release gaba then what am I going to do What I do is release This substance, sorry, subdominant core of inhibition and, therefore, I am going to stimulate it.

If I stimulate it, I will cause it to release a lot of glutamate in this actual neuron located in the globus polito and the gyrus. So this will release a lot of glutamate. If I release a lot of glutamate, what is it going to do to stimulate this neuron? Then it goes in the same direction that it goes to the thalamus and if this is the glutamate that stimulates this particular neuron, these neurons are the GABAergic neuron, so it will release a lot of GABA. What I am going to do to this thalamic nucleus is going to inhibit the thalamic nucleus and if I inhibit that nucleus then I am going to inhibit thecortical nuclei that go to the actual muscles and this is going to inhibit the actual motor movement of unwanted types. of functions, so again this glutamate will be released by releasing glutamate in this gaborga neuron in the globus politus internista, it will stimulate it if it is stimulated, it releases a lot of gaba and it inhibits this thalamic neuron. it doesn't release a lot of glutamate into the cortex if it doesn't release a lot of glutamate into the cortex it won't stimulate the cortical neurons enough and they won't initiate motor movement enough and that might be good for preventing unwanted motor movements this is where the substance comes in again we have these neurons that actually extend up to the striatum the nigrostrial pathway release dopamine now normally what one would think and this is where sometimes it's a little shaky and confusing one would think that our substantia nigra generally the purpose of the niger stradal pathway is increase motor movements, that's the total desire to increase motor movements, but you would think that you would want to increase the desired movements and then inhibit the unwanted movements, right, that's what you would think now. what it's trying to do, but the end result is not effectively the same, so we release dopamine into this actual nucleus here, but here's the difference: this was a d1 receptor, this is a d2 receptor, if it's a d2 receptor, it's an inhibitory protein g that is going to cause an efflux of potassium ions that will inhibit that nucleus, so you can see how the Niagara substance is trying to inhibit the actual inhibitory pathway.

We don't want to inhibit actual unwanted motor movements, but when you do, you inhibit this pathway, so what do you do? Think about this, keep the glutamate the same but have plenty of dopamine. Okay, dopamine will inhibit the skeptic neuron if it inhibits this gobergic neuron. What is the GABAergic neuron going to do? So will it release gaba? Not if it doesn't release gaba. We're going to keep everything black now if he doesn't release gaba, what are you going to do to him? It will release this neuron from inhibition, so it will stimulate it. If this neuron is stimulated, it will send out many action potentials. to the subthalamic nucleus releasing a lot of gaba.

If I release a lot of space in this neuron, what am I going to do? I'm going to inhibit this neuron if I inhibit this neuron. I don't release a lot of glutamate into this neuron if I don't release a lot of glutamate into this neuron. I don't stimulate it enough, therefore it is inhibited. If it's inhibited, then this neuron doesn't actually release much gaba if I don't release much gaba on it. thalamic neuron I release that neuron from inhibition and cause these action potentials to increase and therefore try to stimulate motor movement. The point I want you to understand from this is that all the striatal pathway wants to do, my friends, is increase. motor movement, whether in the direct or indirect route, he really wants us to help him be able to increase the intensity of the movements.

Imagine that a patient has Parkinson's disease. Now destroy the substantial neurons. If you destroy these neurons, what is the overall effect? To be guys, they will decrease motor movement and that's the problem with this particular disease and sometimes when we decrease this motor movement, you look for potential ways that maybe if a person wants to move it's very, very slow and that could be called what if it's very slow movement, it could be called bradykinesia or maybe they don't really move much and it's hypokinesia or they don't move at all in general and it could be akinesia, so these patients can have a lot of difficulty moving. capable of starting, performing or stopping motor movements.

Here's the other thing: You're probably wondering, you're like, well, yeah, I know they're slow and they don't move much or they don't move at all. But they have this a lot, they have tremors and their arms are like lead pipes. What is this about I have you? there's another potential pathway here that's involved from the cortex there's cholinergic fibers and these cholinergic fibers actually go and release acetylcholine into these pathways directly and indirectly this is what I want you to remember it just changes everything that does to dopamine, anything that Dopamine does in the direct pathway, acetylcholine does the opposite, whatever dopamine does in the indirect pathway, acetylcholine does the opposite, so in this pathway dopamine wanted to stimulate the direct pathway, which does acetylcholine Will it inhibit it?

So acetylcholine wants to inhibit this particular pathway. Let's put acetylcholine and this is the indirect route it does. The opposite of what dopamine does in this pathway inhibits it, so it will stimulate it. So what you notice here is in This particular disease has a very interesting pathophysiological process. Let's draw our diagram here. In this particular process we have our caudate nucleus. This is a good summary. I suppose we have our lentiform, which is formed by the external internalist policy of the putamen globe. our thalamus, we have our subthalamic nucleus, all these structures here and then we have our substance.

What you will notice is that the basic pathophysiological principle in this disease is that there are cortical neurons that go here and try to interact, there are substantial neurons. that come here and try to interact and there are neurons that release acetylcholine that go here and try to interact with all these basal ganglia, whether it's the direct or indirect pathway in Parkinson's disease, the substance that does what to dopamine is destroyed. in that striatal pathway, so if I were to zoom in on this particular part of the pathway, I'll hear in a second, what the general theme is here in this disease is that there's a decrease in dopamine in the striatum, there's not enough dopamine.

By releasing that striatum, on top of that, there's also another thing because there's acetylcholine that actually inhibits the direct pathway and stimulates the indirect pathway. It is unopposed, if there is less dopamine here, that will lead to an imbalance between dopamine and acetylcholine and because of that. there is a decrease in dopamine and then acetylcholine is free to be at higher levels unopposed in the striatum. This imbalance, my friends, is what leads to other effects of Parkinson's disease, in particular, the decrease in dopamine in the stratum is what leads to a decrease in movement, but an increase. in acetylcholine it alters the pathways where sometimes they try to fire at the same time where the direct and indirect pathways try to fire alternately at the same time, so if your flexors and extensors contract at the same time tremors and stiffness and that's why in these patients the two particular characteristics is that they also have tremors and stiffness and then associated with this there can also be postural instability and that could be a combination of many different things, but you get the point.

This is the basic pathophysiology of this disease, so my approach to Parkinson's medications should be to find a way to increase dopamine in the striatum and decrease acetylcholine in the stratum for balance. How do I do that? let's talk about those medications, let's talk about their mechanism of action and then we'll go over them in more detail, so what we need to talk about now is what those medications are, let's talk about the category of medications that we can actually use those

drugs

that increase dopamine and then those medications that actually decrease acetylcholine to restore balance, so with those that increase dopamine you can give a particular medication and this is called l-dopa.

We'll talk about this one in particular first, okay, it's one of the most commonly used medications for

parkinson

's and we'll basically talk about how that makes it worse, actually let's just list the category so the first one is l-dopa and the second one, I can give something that's actually really interesting where it's really not. drug because the goal is to increase dopamine so that l-dopa is converted to dopamine. What happens if I give you a medication that doesn't have to use neurons to produce dopamine? I actually just allow it to bind directly to the dopamine receptors, so it's like an agonist, so to speak, let's talk about that dopamine agonist.

Okay, so we have l-dopa and then we have the dopamine agonist. The next one is fine. I can give you dopa, which could convert it to dopamine. I can administer dopamine agonists that will work. like dopamine in the receptors, what if I gave him medications that actually prevent the breakdown of dopamine and help keep higher amounts of dopamine in the neurons or in the synapses so that they can stimulate the dopamine receptors? drug categories here, one is called catechol-o-methyltransferase inhibitors, we'll talk about these and then the other one is called monoamine oxidase b inhibitors and we'll talk about these.

The last category of

drugs

in particular to increase dopamine within this striatum is that I can Give a drug that actually inhibits and increases the synthesis or release of dopamine from substantial neurons, as well as inhibits reuptake, so more is released and less is reuptaken into the neuron, so why is it beneficial if I increase the release and prevent it from returning to the neuron. I keep more in the synapse to reach the dopamine receptors properly. That's the concept here and this is called amantadine which is its own kind of category if that's how you're going to target those things to increase dopamine to be able to improve movement to increase movement the other situation is I can give medications to decrease the effect of acetylcholine for tremors, rigidity, postural instability and that's just being anticholinergic, so these will be my anticholinergics and we'll go over these, like binge trapine and trihexy venado, a little bit later.

Well, with that being said, these are the categories that I want to talk about, what I need to do is Before we can understand each of these medications and a little bit more about them, I want to have the basic mechanism of action, so what we really What I want to do is zoom in on the neurons here in the striatum and what I really want to do is focus on the substantial neurons that act on that gaborgic neuron here in the putamen and then on the cholinergic neurons that act on that gaborgic neuron and the stratum, so I just want to zoom into that and then talk about some of the medications that actually work on that particular pathway, so let's do that.

Here we have our diagram and what we're going to do is zoom in so this is the substance neuron, so we'll call it one, this is actually going to be the substance neuron here, this is going to be the striatal neuron, this is going to be the one that was actually located in the putamen and then into the caudate nucleus and then this will be the cholinergic neuron that was being released coming from the cortex, so we have an idea here, so this is our outline here to understand how these particular medications work and when they work. let's do, let's get closer here so we know that so we can To make dopamine release dopamine there's a particular process involved and that's why it's really interesting, one of the things that happens is we have a particular amino acid that can actually be absorbed. through the blood-brain barrier, so this is actually going to be This represents the blood-brain barrier, which is a kind of capillary structure.

A particular amino acid can be absorbed through the blood-brain system. This is called tyrosine. Now, what happens with tyrosine is that what is called tyrosine can work on tyrosine. hydroxylase now when tyrosine hydroxylase acts on tyrosine it actually turns into l-dopa oh well that sounds familiar. I just talked about that medicine, okay. Great, dopa can be treated by another enzyme called dopa decarboxylase and converted to dopamine. Oh well there it is, there's dopamine and then the dopamine is put into these vesicles via the transporter and then if this neuron is being stimulated it generates an action potential, the action potential will then move down the axon , it will stimulate these voltage-gated calcium channels if these voltage-activated calcium channels are stimulated.

Calcium will rush to this particular neuron. If calcium enters this particular neuron, it stimulates the fusion of this vesicle with the membrane, which then triggers the exocytosis of dopamine, so dopamine is then released. When dopamine is released, it can move through it. the synaptic cleft and it binds to this d1 or d2 receptor depending on which pathway we are discussing, so that's the concept here now, once dopamine exerts its effect here, then it binds to this particular receptor, it exerts its effects Whether through the direct or indirect pathway, we know that after dopamine is removed, what happens is that some of this dopamine will actually go through this special transporter and is reuptaken back into this neuron, so that this is kind of real, let's just call it dopamine reuptake transporter, okay, that's how we're going to abbreviate it, now here is the dopamine that is reuptaken back into the neuron and then from here it can be recycled as we see that the dopamine is recycled here again in the container and then used again, that is a particular way, the other thing is that some of this dopamine can also pass through this transporter and when it is absorbedthrough this transporter it can interact with one of these particular enzymes around the mitochondria this enzyme here is very interesting because it doesn't like to be recycled it likes to break down the actual dopamine and this enzyme is called amine oxidase b you say oh wait I'm sorry I just heard about a drug called inhibitors, yeah you'll see how they come into play here, this actually takes the dopamine and breaks it down and now this dopamine is inactive or sort of non-active. metabolite, so it has no effect, you can't recycle it, so we can't reuse it anymore, so you see how giving inhibitors would prevent that and then we can recycle more dopamine.

Very interesting, well, dopamine doesn't just break down. inside the actual neurons through the enzymes um monominoxidase b, it can also be broken down in the periphery, like I'm actually sorry, inside the synapse, so in the synaptic cleft there is another particular enzyme that can actually break down the dopamine and break it down into Like these molecules, one of the degradation molecules is an inactive metabolite and we coincidentally call it omd and this enzyme here that breaks down dopamine, so it can't actually be recycled, it can't be recycled anymore. can use in the synapse. it's called catechol or methyltransferase, wait zach, you said there was an inhibitor of that, yes, guess why, because if I inhibit that particular enzyme, guess what I'm going to do, I'm going to inhibit it so that it doesn't become inactive into this inactive metabolite. real.

Keep more of the dopamine can be recycled or kept more in the synapse, man, this actually makes sense, doesn't it? We're not done yet, there's something else here, in fact, we'll get to the corner of John's. Lastly, here's the other thing, this is where we run into a problem, so we also have particular enzymes here in the periphery, so let's say I just wanted to give dopamine, I wanted to give dopamine and if I wanted to give dopamine, I give it in the bloodstream, you would expect it to eventually be absorbed by these neurons and then used, you would think that would be the perfect situation to just give dopamine to the patient.

The problem is that dopamine cannot cross the blood-brain barrier. I want to know how we know that, since I told you that l-dopa is the number one agent that we commonly use in patients with Parkinson's disease, let's say I give the patient l-dopa, so I give the patient l-dopa . it has the ability to be taken up by this particular neuron and then again we can bypass the tyrosine and go straight to this step, eventually converting it to dopamine and then using that surge of dopamine into the synapses. Well, one of the problems with this is that L-dopa, only a particular percentage can be absorbed through the blood-brain barrier and an even smaller amount can be absorbed if there is a particular process, so you know there are other enzymes here , there is an enzyme here. that's actually very interesting and can convert l-dopa into dopamine.

I wrote it here, so here is an enzyme called tyrosine hydroxylase, this is called dopa decarboxylase and it stimulates these particular steps, so what do you think this enzyme is? It's just in the peripheral, this is called dopa decarboxylase and it likes to stimulate the conversion of peripheral L-dopa and dopamine. Guess what dopamine can't be absorbed through the blood-brain barrier, so I can't use it, so I have to do it. give a drug that we'll talk about a little bit later to inhibit dopa decarboxylase and prevent it from being converted to dopamine, so that it's pretty much all l-dopa so they can get through this actual blood-brain barrier and we'll talk about it a little bit later, but here we already know that l-dopa can be absorbed.

Here's another problem, not only can this enzyme cause aldobaba to convert to dopamine, meaning less l-dopa is eliminated, but there is another medication. or another enzyme and this other enzyme can actually convert l-dopa into what is called sorry this one is actually called 3 mt excuse me this one is called 3omd now you have an idea this was a comt that converts this in 3mt, so dopamine in 3mt this will convert l-dopa into 3-om-d and this drug is called c-o-m-t, so c-o-m-t also converts l-dopa into these inactive metabolites, an inactive metabolite simply called three om-d Now 3-om-d also cannot be absorbed through the blood-brain barrier, so we can also administer medications.

Now, the interesting thing is that we can give drugs that can inhibit the comt enzyme here in the periphery to ensure that there is more l-dopa. is taken and if we have that drug that can also cross the blood brain barrier, guess what else that comp inhibitor can do? Inhibit the central to make sure that there is also more dopamine present in the synapses and there is one of those. drugs and we'll talk about what's called tulcopone in components is the one that really only acts particularly in the periphery um but here that's the whole concept that I really want you to understand is that l-dopa is one of those primary drugs that can actually They are absorbed by neurons and are converted into dopamine.

In fact, we can prevent l-dopa from being absorbed if dopa decarboxylase acts on it and converts it into dopamine. This cannot be absorbed, so now I do not have the ability to be able to transmit l-dopa or dopamine. In addition to that, if comt acts on l-dopa, it becomes an active metabolite that also cannot be absorbed again, which prevents him from taking eldopa. We'll go over this whole process above when we talk about levodopa on its own, but that's one of the medications, that's how I get aldopa to actually be one of the medications because it can actually be absorbed and used in this pathway to make dopamine. be the other one that I said was dopamine agonist, what if I gave you a particular medication here that actually works specifically here, so it actually crossed the blood-brain barrier, but this particular medication is a dopamine agonist, If you want, can I have this medicine come? and it binds specifically here if it binds to that actual receptor, I can exert exactly the same effect as dopamine on that, this would be the agonist, this is your dopamine agonist, okay, and we'll go over the different medications there, but that's dopamine versus So now we see how we can use L-dopa, so here I'm going to put L-dopa so that we can recognize that this is the first medication that we can actually administer L-dopa and see what it can really be like. used, it can be taken across the blood-brain barrier and then used in this pathway to produce more dopamine.

Well, we can make more dopamine and release more dopamine into the synapse, so there's drug one, drug two, the next one we said are inhibitors. comt inhibitors and mao b inhibitors if I give you a particular medication, like a c o m t inhibitor, it will inhibit this particular enzyme. If I inhibit this particular enzyme, I'm not going to do this particular pathway, so I'm inhibiting the conversion of dopamine. in this inactive metabolite and therefore I am going to allow more dopamine to be present within the synapse by stimulating these particular receptors in the same situation if I give you a medication called monoamine oxidase b inhibitor, it will inhibit this particular enzyme if I inhibit This enzyme will not I'm going to allow the dopamine that is reuptaken or the dopamine that is present in the actual axon bulb to break down, so I inhibit it from becoming an inactive metabolite and allow more dopamine to be present. here in the synaptic bulb, so now more dopamine will be released into the synapse because more will be recycled and into these vesicles, and that means more dopamine can bind to these dopamine receptors quite well from the last one. now it's amantina, manzadina actually does a couple of different things.

Amantadine works to stimulate release, so you see this process where the actual vesicles fuse with the cell membrane, it increases that particular pathway, so you want to increase the fusion of the synaptic vesicles with the actual synaptic vesicle. . with the real membrane and therefore we increase the release of dopamine in the synapse, that is a particular mechanism. The second mechanism is that it will also inhibit dopamine reuptake transporters because if I inhibit these dopamine reuptake transporters, I don't really allow much. I'm not going to allow that much into the gallbladder, which may seem like a bad thing, but remember that if I get it into the gallbladder I can recycle it but I also increase the chances of it being metabolized if I want more. dopamine in the synapses, what if I just inhibit this transporter and now all this dopamine that was actually supposed to be in the actual synaptic cleft is reuptaken?

There is less here, but if I inhibit this transporter now, this dopamine will not be taken. backs off and if dopamine doesn't come back then more of it will stay in the synapse and hit more dopamine receptors so that's the concept of these drugs to increase dopamine whether you give l-dopa and it eventually becomes into dopamine, you just have to be careful because it can be broken down into dopamine in the periphery by dopa decarboxylase or into an inactive metabolite via the comt, so we'll talk about that a little later, we can administer dopamine directly To stimulate the receptors, we can administer drugs that prevent the breakdown of dopamine, such as Mao B inhibitors and comt inhibitors, and we can administer a drug that stimulates the synthesis or release of dopamine and inhibits rheopamine to keep more dopamine in the synapse for the last time.

The situation here is anticholinergics, it's not too difficult, we have muscarinic receptors and there are many different types of muscarinic receptors present here, but I'm going to leave it here that we are going to have muscarinic receptors and we are not going to To go over all the different types, there are five different types of muscarinic receptors. Because you have these muscarinic receptors, when acetylcholine is released from these cholinergic neurons, it binds to this particular muscarinic receptor and, depending on whether it's in the direct pathway, the indirect pathway. We already know the type of effect that it will have if I give you a particular category of medication, like anticholinergics, what anticholinergics will do is they will inhibit this interaction, they will inhibit this particular interaction, so here I want to give anticholinergics because they will inhibit that acetylcholine can exert its effect on the striatal neuron, preventing this excessively high release of acetylcholine.

As you see, the mechanism of action of these medications is really cool, so now what I want to do is I want to go over each of these medications. I want to talk a little more about eldopa. I want to go over dopamine agonists a little more. I want to go over these inhibitors and then amantadine and lastly we'll talk about anticholinergics okay so when we first talk about these drugs that increase dopamine in the stratum, we're going to talk about eldopa first we already understand the mechanism of action, but I think the good thing is to recap this again, one more time. spatial repetition, it's important to keep going over these things, but the basic concept is that when you give l-dopa to a patient correctly, you're going to give it orally when it's given orally, it crosses the gastrointestinal tract when it crosses the gastrointestinal.

Through the tract it enters the bloodstream, so here the l-dopa is now in the bloodstream. Now, when the l-dopa is in the bloodstream, we already talked about how there are two particular pathways, one is that we can deliver l-dopa to what is called three omd and This was done through the comt enzymes. We can also send L-dopa to dopamine, which again none of these can cross the blood-brain barrier and that was coordinated through dopa decarboxylase. However, the goal is to get as much L-dopa as possible. possible at the actual synapse in this area here to cross the blood-brain barrier because again we remember we talked about how we have tyrosine and then tyrosine is converted to l-dopa through tyrosine hydroxylase and then l-dopa is converted to dopamine a through dopa.

The decarboxylase is taken up by the transporters, if there is an action potential for calcium to come in, it stimulates fusion of the vesicles and then they release dopamine and then the dopamine comes out here, it binds to the d1 or d2 receptor and then it acts on this striatum neuron in particular that we already know. It's all good, but what's important to remember is that l-dopa. Whenever you think about this medication, the most important things that I really want you to remember here with eldopa is that l-dopa is really important because one of the most important things that this is going to be your first-line medication now is your first-line medication. , preferably some of the literature will say that you should use this first if the patient is over 65 years old, if you are under 65 years old, you can In fact, I use dopamine agonists again.

I just want you to remember their first-line medication if you want to remember it too. On top of that, it's particularly first-line and for those over 65, but it will be your first-line medication. Here is the important thing because l-dopa has difficulties and can cross theblood-brain barrier because some can actually be converted to dopamine, we should often give l-dopa with carbidopa, so l-dopa and carbidopa are often given together now, you're probably wondering where the heck carbidopa comes into play . I already have the l-dope. I understand how l-dopa is involved here because it is going to work here to increase or stimulate the increase of l-dopa.

We already know where carbidopa comes into play. Carbidopa inhibits the enzyme dopa decarboxylase, so here I have carbidopa and carbidopa works to inhibit. dopa decarboxylase if I inhibit dopa decarboxylase I inhibit the conversion of l-dopa to dopamine, so less of this pathway occurs and I have more l-dopa available to cross the blood-brain barrier, more l-dopa comes through you By producing more dopamine, you release more dopamine into the synapses and stimulate more dopamine receptors, ba-boom, okay, so you see, the point here is that carbidopa, if given in combination with l-dopa, will ensure that more l -dopa crosses the blood. bird brain because it inhibits dopa-d-carboxylase in the peripheral zone, deopodopa decarboxylase is fine and that's also important because the other beautiful thing about carbidopa is that it reduces the amount of dopamine in the periphery because guess what all this dopamine okay, all this dopamine has the ability to produce adverse drug reactions, so if I give carby dopa I prevent more dopamine from being in the periphery, so the carbidopa will effectively reduce the carbidopa will effectively inhibit many of these adverse reactions. to medications associated with the high amounts of dopamine being administered. become on the periphery is not so good, so we have an understanding here, l-dopa, first line agent that really should be given to patients with Parkinson's disease, if you really want, sometimes you can wait until they are al Less than or equal to 65 years of age might be more preferred, but it is the first-line agent and must be administered with carbidopa because it inhibits dopa decarboxylase and prevents it from being converted to dopamine.

Dopamine can't cross the blood-brain barrier, so getting two effects from that is making sure you have more l-dopa to cross the blood-brain barrier and be used and having less dopamine in the periphery to cause adverse drug reactions, that being said , what are some of the adverse drug reactions that can be seen well, one is that if there is a lot of dopamine present, the dopamine has a very profound cardiac stimulation, so I want you to think that quite elevated dopamine is really the problem here, so elevated dopamine is what it can. What it can really do is stimulate the sa and av node system a lot, so it could cause them to fire a lot more, and if they fire a lot more, you'll see a very profound increase in the patient's heart rate.

Therefore, care must be taken with tachycardia or tachyarrhythmias in these patients. The other thing is that there are dopamine receptors that are located deep in the veins, which is really interesting, because there is a lot of dopamine, especially d2 receptors, that are present in our veins and what happens is that when dopamine binds to These receptors in particular cause vasodilation, so the vessel dilates. If it vasodilates, it decreases systemic vascular resistance or actually, more specifically, not systemic vascular resistance, it decreases resistance but it doesn't squeeze the vein if I don't squeeze the vein. I don't squeeze as much blood into the heart, so I reduce venous return, which reduces stroke volume and that can cause the patient to develop orthostasis because every time they have a position, they go from one position to another. another, they do not have adequate venous return and that is why this can lead to orthostasis, so every time the patient stands up or goes from a sitting to a standing position, it can stimulate this orthostatic mechanism because it vasodilates the veins. very deep, well through the d2. receptors and then there are also dopamine and beta receptors that are present in the cardiac system, particularly in the nodal system, and you can see a tachyrhythmic associated with that, so be careful with tachycardia and with postural hypotension or orthostatic hypotension , the other thing is a lot of dopamine.

It's also interesting because when you have a lot of dopamine, there are particular things you have to remember: there are many different dopaminergic pathways in addition to the nigrostriatal pathway, so here is our nigrostriatal pathway that we already talked about, going from here to the basal ganglia. I also have pathways that can actually go and connect to the limbic system, so here I'm going to draw them in green, these will be my limbic nuclei and they could be many different structures, the amygdala, the hypothalamus, mammillary bodies there are so many different structures, but this is called the mesolimbic pathway, so you have something called the mesolimbic pathway and this is a pathway that is associated with your emotions, your reward, your thinking processes a lot of those things, because there is a lot of dopamine that is being released within the mesolimbic pathway can cause many real emotional problems and some of the things that you can see because of this is that you can start to see very unpleasant types of effects here, it can start with the patient as anxiety. and then it can actually bridge quite significantly and it can go on to things like delirium, it can go on to things like hallucinations, delusions, which is terrible and then even progress to a psychosis, so that's why It's kind of scary to think.

What I want to say here is that you really need to be on the lookout for unpleasant adverse effects through the mesolimbic pathway when a lot of dopamine is released within this pathway between the substance and also all the connections like the limbic nucleus like the amygdala like the hypothalamus like mammalian bodies, like the cingulate gyrus, all of these different structures here can lead to increases in anxiety, delusions, hallucinations, psychosis, even sometimes impulse control, so be careful with impulse control as well and impulse control, something like gambling, I'm not even kidding, sometimes it can cause a lot of things. of like loss of inhibition, so these are important things to think about with this, there's one more interesting thing, you know, there's a center here located within the medulla, uh, let's draw this one here and in pink, so this is a center here located within the medulla. and this is actually called the chemo trigger zone, so what is it called?

It's called the chemotherapy trigger zone. Now the chemotherapy trigger zone has many, many dopamine receptors present and therefore we can use particular medications to block those dopamine receptors. when people feel like nausea or vomiting, but if you have a lot of dopamine, that means that a lot of dopamine binds to these chemo trigger zone receptors, the dopamine receptors present in the chemo trigger zone, Guess what that will do if you stimulate the chemotherapy. trigger zone or the ametic center that will cause these patients, you are stimulating the ametic center, this will cause nausea and vomiting, so another particular thing to look out for in these patients is another adverse effect here is nausea and vomiting due to a large amount of dopamine. stimulate the chemotherapy trigger zone, leading to activation of the ametic center in the medulla, causing nausea and vomiting, so now we know that increased dopamine can cause cardiac stimulation, postural hypotension can stimulate the pathway mesolimbic causing a lot of psychotic symptoms or you know.

Delirium-like effects and cause a lot of nausea and vomiting through the medical center in the spinal cord. The interesting thing is that many of these medications increase dopamine in the striatum, either decreasing its pro. You know, it breaks down, either. acting as a dopamine agonist, whether it's all the drugs we talked about that increase dopamine, guess what all these types of effects can have, which is important to remember. The next thing I want to talk about here is the effect of there being too much dopamine because you give too strong a dose or maybe because you have a patient who is taking levodopa and carbidopa with another medication that just increases dopamine too much in the synapses, either way. way, there is too much dopamine present in the stratum.

What is another negative side effect because it can generally increase movement? What happens if you increase the movement too much? Let's talk about that. Well, we already talked about all these pathways here, but the basic concept here is that we had again, the nigrostriatal pathway, which is the dopaminergic pathway of the substances that connect to the neurons in the putamen or the striatal area, and we already know that there were particular neurons here that we already discussed that could go through two paths, one could be the direct path, the other is that it could go through the indirect path and the whole concept here is the same, whether it is the direct or indirect path in this situation , what we know is that dopamine works to be able to do it if it is the d1 receptor. to stimulate the direct pathway or whether it's the d2 receptor to inhibit the indirect pathway, we know that the general theme that we talked about earlier is that it does what increases movement, that's the whole concept and that's the whole beauty of this and that whenever you're increasing movement that's supposed to help patients who don't actually move much, but what happens if you give them too much dose and there's too much dopamine, whether it's such a high dose of carbidopa and levodopa, whether it's because you're giving l-dopa and something else that increases dopamine in the synapse, like you give it with a comt inhibitor, you give it with a mao b inhibitor, you give it with a dopamine agonist, you give it with mantidine. of those things will bring too much dopamine to the striatum, so in this area there is too much dopamine that will increase activation too much and now you get an abnormal increase in movement to the point where it is actually pathological, you would think that would be beautiful, but no, this is a problem and whenever the movements are so intense we call it dyskinesia and what it could look like.

There are so many different ways it can look like some of the things that What I want to think about here is that sometimes patients can exhibit things like chorea, so they have this kind of disorganized movement that they can't control or they have things like athetosis, so they have a kind of snake movement. their fingers can't stay still that's why they have acathya they are super restless these are potential things we are looking at because you are causing too much stimulation of the indirect pathway and a lot of the extra pyramidal symptoms are starting to develop so be careful with this this is a of the things you can really see with high dopamine levels, whether it's giving you too much l-dopa or whether it's l-dopa plus something else that increases dopamine in the synapse like a dopamine agonist or a comt inhibitor or a maob inhibitor, you understand, it's one of those potential concepts that you're seeing here, my friends, we have ac dyskinesia as another potential effect.

There's one more thing I want to talk about. It's actually very important that you can see in your exams that whenever patients are given l-dopa, they can experience something called the on-off phenomenon and it's very simple, the concept behind it is that if you think about it , patients who have Parkinson's disease. Well, let's say here we have just a quick little diagram while you're thinking about this, here's our Niagara substance, that's where the neurons are supposed to go and connect to the striatum. That's the whole concept, as you have Parkinson's disease progressing and progressing and progressing.

What happens with the decrease in the number of substantial neurons is that, as the disease continues to progress, there is a decrease in the number of substantial neurons, which means that there are fewer neurons available for dopamine use, so it does not It doesn't just mean less dopamine, but even if you give a drug like l-dopa if there are fewer neurons, you don't have the nerve terminals to use because remember what you need for l-dopa, you need the terminal to actually come in be converted into dopamine be put in. the synaptic vesicles the neuron to be stimulated and then release it, so that is a problem even though I give l-dopa to patients, I need a certain amount of neurons present to actually use the l-dopa to produce dopamine.

Do you understand what I'm saying? So what we do What we start to see is we see this effect where let's say I give the patient the medication, I give them l-dopa carbidopa, they take the medication, they see a particular effect of the medication for so many hours, then the medication starts. to disappear and then what. It happens that their symptoms come back, so you give them another part of the drug just as the neurons start to be destroyed and destroyed and destroyed, you have fewer dopaminergic neurons available for eldopa, so these symptoms start to develop much faster and patients will take the medication they want.

They'll have this period where they're fine, so they're having good improvement and mobility, they're doing everything right, they'rethey are moving fine but then the medication starts to wear off very quickly and they go into this phase of inactivity. then they have kinesia where they don't move at all and then they are at risk for aspiration pneumonia, all that or they just move very, very slowly, so they come back, which results in a sort of return to their

parkinson

ian phase and then what do they have to do? So they have to give a higher dose, but what's the problem with that, so think about that, here's our dose response curve, so here's my peak efficacy, my emacs, right, remember? ?

This from the pharmacodynamics conference in Parkinson's disease, what we see in the off phase where it happens is that we see that there are a substantially smaller number of neurons, which means that there are fewer neurons available for dopamine, even if we maintained the same dose. In this patient when we are in the shutdown phase, they are running out. Well, the drugs are running out. What we noticed is that even with the same dose we noticed a decrease in e-max. Look at the e-max. Now the e-max has decreased, so in this situation. here we notice a decrease in the effectiveness of the drug there is a decrease in the effectiveness of the drug and the reason why there is a decrease in the effectiveness of the drug is because the number of neurons is decreasing and they do not have enough neurons available to be able to use the aldopa to produce dopamine, so what would you think?

Oh well, what I could do is if I increase the dose, that would work fine, so let me go ahead and just increase the dose, so now here on the x. the axis is the dose on the y axis is a response the response depends on the l-dopa the dose of l-dopa but it also depends on the number of neurons that is what we have to remember I can't change this but I can change the dose and then you think, oh here we go, this is what I'll do: I'll increase the dose and if I increase the dose I go this way maybe I'll reach maximum efficacy, but if you remember our pharmacodynamics conference Yes, we can get to that maximum efficacy, but as As I start working lower and lower in this dose range, what increases the risk?

I increase the risk of these toxic doses, so now I'm starting to get into the realm of negative side effects because As I increase the dose of my l-dopa, I'll see more dopamine in these synapses, I'll see more of the dopamine effect in the heart, I will have more dopamine in the mesolimbic system. via more dopamine I see more dyskinesias so as the dose increases I will see an increase in adverse toxic drug reactions so I can't increase the dose too much, I may be able to increase it a little but what can I do? Instead, what I do is keep the dosage the same so I don't have so much l-dopa that it turns into dopamine.

What happens if I keep the dosage exactly the same but give it more frequently to patients who have what is called on off? phenomenon, so let's write this down here, the on-off phenomenon, which is basically when the medication is working, it's working on those actual synapses, it's taken up by the neurons, it's working to be able to improve your symptoms and then as the drug wears off, it can start to happen very, very quickly as the number of neurons decreases, this deactivation phase will kick in very, very quickly, so the drug won't last very long and so you think, well , the ethics are decreasing if I reduce my dose.

It will increase the effectiveness, yes it will, but then you will end up with adverse toxic reactions to the drug, so the ways that I can prevent the off phase to prevent the drug from wearing off quickly is that I could do a couple of things, one of the options here is to decrease the time intervals, so instead of giving it to him, I just retrieve it every three hours. Sorry, every six hours, I give it every three hours, so I increase the frequency of dosing the medication. Here is another option. Another option is that maybe it will hit him.

This medication, l-dopa, in combination with something else that prevents its breakdown or acts as such, just doesn't cause as much l-dopa to be converted to dopamine, so I give it something else besides l-dopa. Oh, that's a great idea, so let me. give l-dopa plus something that doesn't actually make aldo turn into dopamine, so anything else I can get with a dopamine agonist, I can give it with a comt inhibitor, I can give it with a maob inhibitor, you get the picture point. I can give l-dopa and carbidopa with any of the other dopaminergic medications because what that will do is help you be able to increase dopamine in the synapses or have a medication that acts the same as dopamine without having the toxic adverse effects. dopamine effects, you get that point?

That's the benefit of this, so to reduce the off phase in the on-off phenomenon as the number of neurons of the substance die, you have fewer synapses available for less dopamine, you would think if you increased the dose. It will work, but I will give you toxic ads, so what should I do? Decrease the time interval and keep the dose the same or administer l-dopa in a combination of other dopaminergic medications, such as dopamine dopamine agonists, cmt inhibitors, mao b inhibitors. and I couldn't include it here, but also amantadine, okay my friend, so now let's go over this, I'm not talking about agonists, so we already covered l-dopa and carbidopa, thank goodness, they are not difficult names , doping agonists, let's move on Okay, so here we know that tyrosine can be absorbed into this neuron.

Tyrosine can be converted to L-dopa, then it can be converted to dopamine and then dopamine can be absorbed into this vesicle and stimulated through calcium. causes it to fuse with the cell membrane when it fuses it releases dopamine here in the synaptic cleft which then binds to the d1 or d2 receptors of the striatal neuron we know these things what if I gave you a drug that didn't have to go away? Through this pathway, what would happen if I gave you a medication like a dopamine agonist that had the ability to cross the blood-brain barrier and then go directly here and stimulate this dopamine receptor just like dopamine would?

Wouldn't that be amazing? can produce exactly the same effect theoretically, yes, so what are some of these dopamine agonists you ask? Well, some of these dopamine versus that I really want you to know, so there are two different categories, so to speak, one is called ergots and these have a lot of unpleasant side effects that we will discuss, but there are two in particular here and we don't really use them anymore. , one is actually called, we're just going to write one down because the other one we don't even use them at all so it's actually just bromocriptine, so bromocriptine is no longer used for patients with Parkinson's disease.

Well, there is another group of dopamine agonists called non-ergots and these have fewer actual toxic side effects than bromocriptine. There are two in particular, I want you to know pramipaksol and the other one is called ropenerole ropenerol. Now these two medications in particular, uh, again, your primary paxon rapinroll without ergots will actually be interesting medications that we can use in patients. Let's even consider this as a first-line agent and patients under 65 remember why we said levodopa is technically the first-line agent, more particularly in those over 65, we can actually use this is a real alternative to l-dopa carbidopa in minor patients. 65 years old, so we can use this, let's write this down, it can be considered a first line in patients under 65 years old, which is interesting now that when we give these drugs we know that they stimulate dopamine receptors, so they will produce exactly the same effect on the direct pathway and the indirect pathway will improve movement, that's all these medications will do, so leave a dopa carb dopa, remember all the medications out there are just trying to improve the onset of movement, they are improving bradykinase, hypokinesia, aquinasia. etc., they don't really do much for the tremors and rigidity that anticholinergics will.

One of the most important things to think about with these particular medications is that they again increase dopamine in the central nervous system. Well, because they do. increasing dopamine in the central nervous system, you can see some of the similar effects that we talked about with l-dopa and what that might be. Well, let's note here if it acts here in its mesolimbic pathway if it works in the mesolimbic pathway What are we going to see? Let's look at all those behavioral effects. So one of the things we could potentially see here is behavioral changes. The behavioral changes are due to the mesolimbic pathway so you are increasing dopamine in the mesolimbic pathway we could also see what else we could also see what other adverse effect here we can see emesis correctly so we can see nausea and vomiting and this It is through the path that here if I had to draw here another little very complete diagram here we are going to have the spinal cord, what was that structure that I drew here in the spinal cord, the trigger zone for the chemotherapy?

This could be due to stimulation of the ametic center within the marrow or the chemotherapy trigger zone. get the point here, so you're stimulating these limbic pathways or you're stimulating the drug within the spinal chemotherapy trigger zone that causes nausea, vomiting, so you get the same effects that you would get with eldopa, you just don't get as much cardiovascular effect . effects such as postural hypotension and tachyocardia because you are not going to have as much dopamine in the central nerve, I feel it in the periphery, the next thing here is that you can also have something very interesting, but we see this particularly more. with ergots so that non-ergots and ergots who can see these central nervous system effects through the mesolimbic pathway through the medical center in the medulla, they may see a mild degree of postural hypotension, they may see a very mild degree of postural hypotension. tachycardias, but not as many compared to levodopa hornbeam dopa, so with these things with ergots you can also see two other particular effects that I want you to remember: it can actually cause a lot of fibrosis of the heart tissue and lung tissue and So , because you may see a degree of fibrosis and vasospasm, that is, fibrosis and vasospasm of the particular structures present within the lungs and in the heart tissue, so be careful with that as well, so we have dopamine against again ergots, bromocriptine, non-urgots, premipaxol and rapinorol, these are the particular first line agents that we use, we do not use ergots because of the pulmonary and cardiac fibrosis, retroperitoneal fibrosis that they also cause, but these can be first line for people under 65 years and again, just be careful because it has the similar side effects that l-dopa does as well, well, let's move on to the next two categories of medications that prevent the breakdown of dopamine through particular mechanisms, such as comt inhibitors or mao b inhibitors, so it's the same concept here guys.

So we have the same concept here again: you have l-dopa or tyrosine, whatever it is, this is being absorbed correctly, so we have tyrosine, which can be converted to l-dopa and then the dopa is converted to dopamine, which can being absorbed by the vesicles, calcium enters, stimulates these vesicles to fuse with the cell membrane, releases dopamine into the synapse, dopamine binds to the d1 d2 receptors and then acts again on these stratal neurons to produce the effect in the direct pathway. and indirect by improving movement right now with That said, we know that the dopamine that is here in the sonophagus synapse can also try to be reuptaken correctly so that it can be reuptaken through the reuptake transporters, but we also said that it can actually be break down. and is converted to an inactive metabolite called 3mt.

This is an inactive metabolite. This is done through an enzyme called comt catechol omethyltransferase. Now I also told you that l-dopa is also interesting because in the actual periphery it doesn't cross, so here's the blood-brain barrier. we have an enzyme, a comp enzyme in the central nervous system and we also have a comt enzyme here because remember I told you that l-dopa can be converted into what is called 3omd and this was through the comt enzyme, so There are two of these enzymes. one on the periphery and another in the central part. Now what I want you to know is that when we give these particular drugs to the clmt inhibitors, what we are doing is inhibiting these particular enzymes, as we talked about before, so we are inhibiting this and allowing more L-dopa to be present. to cross the blood-brain barrier.

Making more dopamine increases dopamine in the synapse. That's one way and the other way is we're inhibiting it from breaking down, so we're inhibiting it. this route and allows it to decompose lessdopamine and increases the amount in the synapse, maximally stimulating these dopamine receptors. The last thing here when we talk about these particular medications, the cmt inhibitors, it is important to remember that there are particular medications that are going to inhibit the central comts and then those that actually inhibit the peripheral cmts, what is the name of the inhibitors of co2 cont that actually inhibit the central comt enzyme?

You know this is called tolcopone, so tolcopone will be one of those. particular medications that inhibit the central comt, so they help to be able to increase the dopamine present in the synapses, but you know what else is interesting, tocopone also inhibits the peripheral, so we have tolcapone and another medication here called capona and these inhibit the peripheral comt and that allows more l-dopa to cross the actual blood-brain barrier into the actual adrenergics and into these actual dopaminergic neurons to become dopamine and release more dopamine into the synapses, either wayWhat you're noticing here is that the tocopone can increase the actual dopamine present in the synapses, but the only problem is that this is superiorly hepatotoxic, so tolcapone is extremely hepatotoxic, okay, it is extremely hepatotoxic for that and you see this way more. specifically with tolcapone, we don't use this medication often for that reason, so the only real option we commonly go to is the component alone because of the unpleasant adverse effects that Tocapone has on the liver, so taking capone really is the best.

The only job it would do is increase levadova uptake and increase the amount of dopamine in the actual synaptic neurons to allow more L-dopa within the actual synaptic cleft. If you could administer tocopone, yes, it would increase the dopamine inside. the actual synaptic cleft as well, so many times the true indication for these particular medications is that they are an adjunct to aldopa and carbidopa, and really the only use for these medications is that they are commonly administered intermittently. phenomenon, then when those patients are in that off phase and we don't want to increase the aldopo medication or we have already reduced the time intervals and given it more frequently and we are at that point where we need more effect because the patient still has hypokinesia akinasia dyskinesia, so what we can do is add that to the levodopa carbidopa and give it in combination to allow more oily dopa to pass through the actual blood-brain barrier as well as increase the amount of dopamine present within the synaptic cleft, that's the concept here now because they help to increase dopamine.

Guess what you're going to see with these, the same adverse effects you would see with l-dopa or dopamine. agonist, so the adverse effects to be aware of here are definitely hepatotoxicity with tocopone, but also be careful again with nausea, vomiting due to stimulation of the ammonite center in the medulla, and behavioral changes due to possible changes in the mesolimbic pathway, so behavioral changes. And again, there are also other things you need to think about with these particular medications. Okay, that covers the cmt inhibitors. Now let's move on to the next one, which is Maob inhibitors. Okay my friend, now they will be inhibitors, so it's the same thing. concept here we are trying to inhibit the breakdown of dopamine, that's the whole concept: increasing dopamine present within the synapses or recycling more dopamine, whatever, maybe, so we talk about cmt inhibitors, we talk about how they improved l-dopa around the world. uptake of the brain barrier or how they helped to be able to prevent the breakdown of dopamine in the synaptic cleft of the right talc bone in component with these mao b inhibitor drugs, because you know that there are actually two different types of monoamine oxidase, monoamine oxidase a and monomine oxidase b.

We'll talk about that because potentially the adverse effects that we can see from these medications as well, but the basic concept here, man, this will already be burning your brain, so the l-dopa is transmitted when it passes through the blood-brain . barrier we know that we have tyrosine and that tyrosine can be absorbed and converted into l-dopa. The l-dopa can then be converted to dopamine and then the dopamine can be absorbed by these vesicles if the calcium ions enter when the calcium ions enter. They stimulate these actual vesicles to fuse with the cell membrane when they fuse with the cell membrane, they release dopamine into the synaptic cleft.

Dopamine then binds to dopamine 1 and dopamine 2 receptors and stimulates this potential striatal neuron and inhibits tension in the neuron. Now we know. this particular concept here now here's the other thing, remember I told you that dopamine can actually be broken down, so sometimes what can happen is that dopamine can, when it finishes working properly, dopamine can break down. absorb through reuptake transporters, so perhaps it can be taken. up through reuptake transporters here we can use this potentially here we have our blue transporter here so let's use that side but here we know that when dopamine finishes exerting its particular effect here we know that dopamine can be absorbed through these transport of Dopamine reuptake, we just abbreviate it that way now, once the dopamine is in, we know that they can actually be taken up by the vesicles and potentially reused.

The same concept whether dopamine has been reuptaken or whether dopamine is present within this area of ​​the actual body. terminal bulb of the axon because it is being synthesized, what can happen is that dopamine can be acted on through these enzymes present in the outer membrane of the mitochondria and these enzymes are called monoamine oxidase b enzymes, so the monoamine oxidase b enzymes and What they do is they take the dopamine that is recycled or the dopamine that is synthesized independently and then they break it down, they actually turn it into an inactive metabolite and effectively that means that you have less dopamine that can be recycled and taken to this vesicle or less dopamine that Being synthesized and brought to this vesicle in any way, it reduces the amount of dopamine that is present in the synapse to act on these neurons, so if I give you a particular medication, such as a MAO-B inhibitor , what these mao-b inhibitors do is that these medications inhibit. this particular enzyme, if this maob inhibitor inhibits this particular enzyme, it will not allow it to take dopamine and convert it to an inactive metabolite, therefore more dopamine that is synthesized or recycled enters the synaptic vesicle and more dopamine is released . released into the synaptic cleft that acts on neurons in the striatum.

You get the point: we are increasing the actual amount of dopamine available in the synapses by preventing its breakdown. What are the different medications that fall into this particular category? So, there are two medications in particular. which are maob inhibitors, one is called celagine cellageline and the other is called resagiline. These are the two medications in particular that I want you to remember are MAOV inhibitors. Many times when we administer these particular medications, they are not actually first-line agents. We actually don't even give them much anymore, but one thing to remember with these particular medications is that they're often an adjunct to levodopa and carbidopa, a lot of times in an on-off phenomenon because again it's just going to help allowing more dopamine to be present in the synapses by preventing them from breaking down, is sometimes possible and this is again a textbook answer: you can use it in the less severe cases and in the milder cases of Parkinson's disease, but many Sometimes we just don't do it.

This is not typically prescribed as a very common monotherapy agent, so again, it's important to remember that it's usually an adjunct to levodopa and carbidopa. In the true textbook literature, it can be used in very mild cases of Parkinson's disease, but many times it is not really a monotherapy agent, that is the most important thing we need to remember about this medication now, when we talk of celadeline and Risageline, generally as a supplement to leave a dope carburetor to prevent the shutdown phenomenon or the shutdown effects of the on-off phenomenon, things that we can also think about this, are the adverse effects.

This is where I told you that there are two enzymes in particular, so in this I'm going to draw this here in blue. This will be a particular enzyme that will be present in the mitochondria and this will be called the enzyme monoamine oxidase and then here in red we are going to have the other one here which is called monoamine oxidase b and we already know what monoamine oxidase b does well, we know that it basically takes the dopamine that it's present in these vesicles and then it inhibits it and converts it into an inactive metabolite, monoamine oxidase, it's basically responsible for breaking down things like norepinephrine, epinephrine, and 5-hydroxytryptamine, which is serotonin, so it's basically responsible for breaking them down. into inactive metabolites, so if when giving a monoamine oxidase B inhibitor, what's important to remember is that they are very selective, so they will inhibit monoamine oxidase B, they will inhibit the breakdown of dopamine, and therefore they will try to increase the dopamine in the central system. nervous system, the adverse effects that you would see here are all the things that we talked about about the increase of dopamine in the central nervous system, so we already talked about this, that the adverse effects of this would be nausea, vomiting due to the stimulation center of amethyst or it could be due to behavioral changes through work in which situation the mesolimbic pathway else in very high doses these monoamine oxidase b inhibitors lose their selectivity, so in very high doses monoamine oxidase b can be inhibited. so these are very high doses of monoamine oxidase B inhibitors, very high doses because they are very selective when that happens, you inhibit these enzymes, they do not break down norepinephrine, epinephrine, 5-hydroxytryptamine, oh my God, can you imagine the disaster with this? leads to two potential things: one is if you have massive amounts of norepinephrine and epinephrine circulating through your bloodstream, oh my goodness, hypertension galore, so you will see a hypertensive crisis as a result of this, especially if the patient takes this with tyramine , so remember this.

It can also be greatly exacerbated if taken with tyramine or some other agent, okay, some other potential drug in particular, but in general, tyramine is the common example they use on forums, it can also increase serotonin levels and so That can lead to something. It's called serotonin syndrome and again you see this usually in combination with a tricyclic antidepressant or an SSRI or something else in combination with this MAOB inhibitor, but you get the point is that often these MAOB inhibitors actually cause side effects similar to those of him -dopa potentially within the central nervous system because again what they're doing is increasing dopamine in the synaptic clefts, meaning the medical center synaptic clefts in the medulla, the synaptic clefts in the mesolimbic pathway, but at high doses. has lost its selectivity inhibits mao inhibitors a increases norepinephrine, epinephrine and serotonin, leading to hypertensive crises, especially if taken with hieramine or serotonin syndrome, especially if taking the amylb inhibitor with a tricyclic antidepressant or ssri okay that covers the maob inhibitors now let's cover the The last drug I want guys remember it increases dopamine within the synapses and that's amandine okay so amantadine amantadine is an interesting drug , but again, I swear you will know this way in and out, but even though I can cross. the blood brain barrier, when you remember, we have tyrosine which is actually converted to l-dopa and then the l-dopa can be converted to dopamine and then the dopamine can be absorbed into these vesicles when the dopamine is taken up with the vesicles and then the calcium goes away. to be brought to this neuron through an action potential, it will stimulate these dopamine vesicles to fuse with the cell membrane.

Release dopamine into the synapse. Dopamine will bind to the d1 d2 receptors and exert its effect on the striatum neuron at this time. We've already talked about comt inhibitors, mao b inhibitors, we've talked about dopamine agonists, and we've talked about levodopa carbidopa. Now the next thing we have to talk about is amantadine. Amantine is really interesting, so what amandan does is again when dopamine is brought into the synaptic cleft. One of the things we know is that it can be re-entered through this transporter, so it can be re-entered through this dopamine reuptake transporter. I'm shortening it now.

The problem with this It may seem like a good thing, true, it may seem like a good or bad thing, when dopamine returnsto this actual axon terminal, two things can happen, one is that it can return to the vessel and be reused to be returned to the synaptic cleft or the dopamine can be absorbed when it is recycled through the mao, as we just talked about, it can be broken down by the maob enzymes and that can basically make it inactive and it can't be reused, so the best situation is really to prevent dopamine from being reuptaken in general and just keep it in a synaptic cleft, so when we give drugs like amantadine, what amantadine does is two things in particular: amantadine will stimulate synthesis. of dopamine is going to stimulate the release of dopamine and amantidine is also going to inhibit the reuptake of dopamine either way if I stimulate the synthesis if I stimulate the release of dopamine I will have more dopamine being pushed to the left synaptic If I inhibit the reuptake of dopamine , then I don't make the dopamine go back to the synaptic terminal to be reused or broken down, so I make sure that most of that dopamine stays here in the left synaptic.

Either way, there is more dopamine to bind to the d1 d2 receptor and it exerts this effect on the striatum neuron now why would you give it anthony? amanda dean is actually very interesting, it's actually been found to be neuroprotective, so it's been found to be neuroprotective, it may actually slow degeneration slightly, it's not proven. There is evidence for this, but it may actually slow the neurodegeneration of particular nigrostriatal neurons, so it's actually very interesting when it comes to that, so there's a question about whether this neuroprotectant is a neuroprotectant. The other thing is that it's not actually a solo agent, it's an adjunct, so this is also a two-l dopa carbidopa add-on, but here's another situation where you could say yes, it could be using the on off phenomenon. , but I'm talking like a super off phenomenon, so there is a very interesting situation where someone can have what is called a kinetic crisis, so usually this happens when someone I don't know just for some reason stops take your l-dopa carbidopa, you stop it, you've been off it and you stop it abruptly and now you're off it for normally for a longer period of time than you normally should be because you're not getting doses of l-dopa and carbidopa, you're in this period of inactivity, but if inactive for a long period of time, this can reach the point where the patient does not move at all, does not move the face, does not move many other muscles that help him breathe, does not move the muscles to push blood towards your actual heart, etc. that during a kinetic crisis patients are at high risk of DVT, they are at high risk of pulmonary aspiration, which increases the risk of pneumonia, they are also at risk of hyperthermia, so there are really unpleasant complications that can be seen in a kinetic crisis. so in a kinetic crisis what we should give patients is levodopa carburetor, we would give them back the dose that we stopped or that they didn't take for some particular reason and we would give them amantadine and then sometimes we can also give them one more drug in a kinetic crisis, if you really want to know, it's a bromine, it's a dopamine agonist, particularly one of the non-ergot ones, we just don't use it often, but there is one more drug, so we can give three drugs in particular and one of kinetic crisis.

We give him back the l-dopa, one two, we give him amantadine and the last drug is the dopamine agonist, but it is very powerful. It's called apomorphine, and again, it's often used in patients who are having a kinetic crisis. Another interesting thing. about amenti, it's also an anti-influenza agent, which is pretty good, but the general concept is that anthony may have some degree of neural protection, but there's not enough evidence to fully support that, at this point, it can be used as an adjunct to levodopa carbidopa, particularly in patients who have a kinetic crisis, there has been an abrupt discontinuation of their levodopa carbidopa and they are not moving at all at risk of dvtpe hyperthermia and ammonia aspiration.

Restart your levodopa carbidopa, add mantidine and then you can. I also get a very powerful dopamine agonist called apomorphine and this is usually used in patients with a kinetic crisis now because amantine is not really a single agent, we don't usually give it as monotherapy, it's usually an adjunct, what are they? the possible adverse effects? It's a really good drug that doesn't have a lot of toxic side effects, which is good, it increases dopamine in the synapses, so obviously you have to be careful with any kind of increase in dopamine in the central nervous system, so still You have to be careful. very mild, very, very mild, nausea, vomiting, very, very mild, behavioral changes, so you don't really see a lot of these things compared to all the other things, but you still have to be careful with that because of the high dopamine in the central nervous system, but other things.

What can potentially be seen within this disease can actually have a large effect on the cerebellum and therefore can lead to ataxia. It can also have an effect on the skin and cause something called reticular libido and last but not least it can also cause some edema in the periphery so be careful with peripheral or pedal edema and that is something what you should think about with amantadine, so again amantidine will increase the release of synthesis and prevent the reuptake of dopamine, improve it within the synapse. Can be used as a complement. leaving a double carbide open and a kinetic crisis in combination with giving the patient back his l-dopa and apomorphi.

Now we're talking about it, let's finish with the last category of medications to restore the balance between a decrease and an increase in dopamine. in acetylcholine, what are we going to give? We have already administered all the drugs to increase dopamine. Let's give medications that can really decrease the effect of acetylcholine. Anticholinergics. Okay, anticholinergics. So we have to restore that balance. My friends. So there was a decrease. in dopamine and there was an increase in acetylcholine, so really when we give these particular medications, the anticholinergics have nothing to do with the dopamine pathway, so they have nothing to do with this, so the problem with this disease is that there is a decrease in dopamine, there is a decrease in the presence of dopamine within the striatum and because of that effect of the loss of dopamine on the d1d2 receptors, these patients develop a decrease in movement, we know this, but the Another situation here is that because there are also neurons that release acetylcholine, there is also acetylcholine. will be released and there will be a large amount and by acting on these cholinergic receptors, these muscarinic receptors, this will lead to what can cause tremors and this can cause rigidity, so in this situation we can use it as a monotherapy agent in patients who have very many tremors and a lot of stiffness, what are these particular agents?

Because the only thing these agents are going to do is use these bad boys to get in there and block the acetylcholine so that it can't bind to the muscle receptor, therefore it won't alter the effect of the direct pathway and the indirect pathway and that's why we will inhibit the tremors we will inhibit the effect of virginity what are these particular agents there are two agents in particular that I want you to know one is called benzotrapine, one is called benz tropine, also known as cogentin and then the other one is called, this is an amazing name, trihaxi phenyl, oh my gosh, okay, so these two particular medications here replace trapine with hexa trihexy phenyl, they work as an anticholinergic or muscarinic antagonist you guys probably remember this, we talked about this in the video on muscarinic antagonists.

These will help restore the balance between dopamine and acetylcholine. If I restore that balance, I will prevent the tremors and the stiffness within this disease, so if guys, remember we should, it shouldn't take too long, this shouldn't take too long, what are the adverse effects of anticholinergic agents, so, What would it do to the central nervous system? So, adverse effects, here we go, first the central nervous system. It can cause delirium, right, what would it do to the pupils if we examined them again? What does the parasympathetic nervous system do once it causes constriction in people?

So you're going to oppose that. What will cause dilation in people? So it can cause dilation of people, so people will be big, what else can it do to the glands? can decrease salivation, can decrease tearing, so it will cause dry eyes, dry mouth, dry eyes and mouth, what does it do to the cardiac system, what does a parasympathetic nervous system generally do to you? your heart? You want to slow things down, so they will actually oppose that, so it will increase the heart rate and cause hypertension, so it can cause tachycardia and then cause hypertension.

The next thing I want you to remember is that if you remember we talked about the sympathetic nervous system generally releasing norepinephrine epinephrine, but there is a situation where it acts on the sweat glands, it releases acetylcholine and when it acts on the acetylcholine of the swell the acetylcholine acts on the sweat glands, it will actually induce sweating, so if we gave a medication that actually blocks acetylcholine in the sweat glands, what would that do to prevent sweating? So if I don't sweat, I can't really cool off. downward is because the patient develops an increase in body temperature, so he may have hyperthermia or pyrexia, what else can act on the git?

So what do you do to the git and then the urinary system in general when you are in a parasympathetic situation that you want? to allow for digestion at rest, so you want to be able to defecate and urinate, so in this situation I'm going to oppose that, so I'm going to inhibit defecation, something called constipation and I'm going to inhibit urination, I can cause retention of urine, the other thing is that it can actually cause constipation and it can also cause urine retention. I know you guys remember all that from the muscarinic antagonist video, but that's just a quick reminder, so now, my friends, we've talked.

This video talks about everything you can imagine with Parkinson's medications, but we are not done yet, let's do at least one case to understand this. Well, my friends, let's ask some case questions here, so the first is a 75-year-old man with moderate illness. Parkinson's disease no longer responds to anticholinergic treatment mainly for tremors, not so much for bradykinesia. Again, bradykinesia is not as well treated by anticholinergics as it is by drugs that increase dopamine. In these situations, if we reduce the effect of acetylcholine, we obtain a greater reduction in tremors. and the rigidity factor not so much bradykinesia, so at this point we must devise a good treatment plan for the patient to help with bradykinesia and the first line is always levodopa, generally patients over 65 years of age.

We always started levodopa if they were under 65 years old and it was a milder case, we could consider dopamine agonists like Laura Penerol or Premy Pax all things of that nature, but since this patient is already 75 years old and has already been treated with the anticholinergic for tremors and they already have bradykinesia and are more of the moderate state I am going to go for the first line which is levodopa so if we look here I can tell you that the answer has to be b oh and I just clicked in it but we know that it is going to be this because there is no other option here that we see for levodopa it has to be levodopa and you always have to give levodopa with carbidopa because when you give carbidopa it reduces the ability of levodopa to convert into dopa or dopamine because the Carbidopa is a dopa decarboxylase inhibitor, so you have to give levodopa with carbidopa and it was literally the only option now.

The other reason we can give that other drug that's in capona as a component is again, a comt inhibitor, particularly a peripheral comt inhibitor, so when you give these two drugs, think about it, you're going to give him levodopa. Levodopa wants to cross the blood-brain barrier. Carbidopa will actually inhibit dopa decarboxylase so that levodopa is not converted to dopamine. The second thing is that levodopa can also be broken down by comt inhibitors in the periphery into 3 or an inactive metabolite that cannot cross the blood brain barrier and if I give you a comt inhibitor I will inhibit that process and make sure that levodopa essentially crosses the blood brain barrier, so this is a great combination to ensure that actually all of the levodopa gets through, nothing is converted to dopamine, nothing is converted to 3md and this is actually a great pill that really comes. in a combination pill, I think they actually call it um stelivo, so it's one of thosemedications that can actually come in a combination form that is nice and easier to adhere to, so that's the second question, the peripheral adverse effects of levodopa include nausea, hypotension and cardiac arrhythmias and this can be lessened by including which drug and therapy we will remember when we talk about levodopa causing nausea or vomiting by stimulating the trigger zone of chemotherapy, hypotension by acting on the dopamine receptors in the blood vessels, dilating them. and cause orthostasis and cardiac arrhythmia acts on the beta receptors in the heart to increase heart rate, we are actually talking about dopamine and if I gave him levodopa and I didn't give him any carbohydrates, guess what most of the levodopa would converted into dopamine? so it causes nausea, vomiting, hypotension, cardiac arrhythmias, what medication would inhibit the conversion of levodopa to carbidopa, sorry, to dopamine, it would be carbedo, it somehow gave you the answer, but again it has to be carbidopa here because the Carbidopa reduces the ability of levodopa to convert to dopamine and it is that excess dopamine in the periphery that causes these cardiovascular effects and nausea.

Well, it wouldn't be amantidine, it wouldn't be arrepentol, it wouldn't be capona. Well, all of this could actually even cause these effects as well because they increased dopamine. Well, let's talk about the next one here: which antiparkinsonian medication can cause vasospasm. I went over this briefly in the video. Remember that I told you that there are two types of dopamine agonists: ergots and non-ergots and ergots that we don't use as much anymore, like bromocriptine and pergolide, and the reason is because they can cause pulmonary and cardiac fibrosis, but the other thing I briefly mentioned is that they can actually cause vasospasm, this can actually cause patients to like losing some of their fingers or toes because it can really constrict their vessels and can cause erythromalacia.

It can actually cause fibrosis and necrosis of the fingers as well, so we don't really use bromocriptine and pergolai for that. There is no reason anymore and that is why we prefer premie paxol and rapinterol, which are not ergots because they do not have any vasospastic effect which they do not have and it is also important because they can actually cause vasospasm of the coronary vessels like Well, that would be problematic If you have coronary vasospasm, what could increase the risk? It may increase the risk of a myocardial infarction or some type of angina as well, so be careful with bromocriptine, especially if the patient has underlying coronary artery disease.

I want to avoid that medication so I would definitely be here in this situation, bromocriptine and if if it was there pergolide it would also be percolite so that would be that option so again it covers all of these questions that we need to quickly summarize what we talked about here about Parkinson's medications and Parkinson's pharmacology. I hope we made sense. and I hope you enjoyed it as always until next time