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0:07
what's up ninja ner in this video today we're going to be talking about Parkinson's medications or the pharmacology in Parkinson's disease there's a lot to discuss before we get started if you guys really do benefit from this video it helps you really do understand some things after this please support us and the best way that you can do that is by hitting that like button commenting down the comment section most importantly subscribe also down the description box we do have links to our website we on there we have some awesome illustrations some great notes that you can follow along with during this process so please check it out all right let's start talking about these meds though so I think the first thing that we have to do before we can really understand the different names of the medications and the mechanism of action and some of the adverse effects the classic way that you should talk about pharmacology we really need to have a good understanding about the basic path
0:53
of physiology the anatomy some of the pathways that are involved within the circuitry involved in Parkinson disease before we can really go through the mechanism of action so let's briefly do that I don't want to spend a ton of time so I kind of want to blow through this relatively quickly if you guys want more detail on this go watch our video on the basil ganglia where we go over all the anatomy all the circuitry and way more detail we're going to kind of go through it a little bit quicker Pace to build our foundation though so when we talk about the anatomy of the basil ganglia here we have abbreviated BG there's a couple different structures one of the first one that I want you guys to remember here that I'm going to kind of color here in this pinkish color is is called the kodate nucleus okay so this is called the kodate nucleus now there's a couple other gray matter structures that are just situated deep within the cerebral cortex right so here in this
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area of kind of like the Dian sephylon we have another structure that I'm going to draw here in this orange color so let's do it orange this is actually going to be the linty form nucleus and there's three components of it this component out here is going to be called the pamin this one in here the two components is called the Globus palatus there's two parts the Globus palatus externus which is going to be this component here and the Globus palatus intern so let's again let's remind ourselves what these structures are here again we're going to have this whole thing is the linty form nucleus and it's made up of the pamin globous pitus externus globous pitus internis good all right another particular structure let's draw this one in blue is going to be these egg-like structures that sit here in the center these are going to be called your thalami so each one is a Thalamus so we have Cotate nucleus we have the lint form nucleus and we have
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the thalamus and again the lint form is the pamin Globus pitus externus and internis all right couple more structures almost there next one is there's a structure just underneath the thalamus we're going to draw this is like this box just underneath the thalamus this is called the subthalamus so the subthalamic nuclear also involved in the structure and there's one more and super critical to understanding Parkinson's disease in the midbrain so here we're in the midbrain there is these structures here which we're going to highlight here in Black this is going to be the substantia the substantia okay now in Parkinson's disease there is destruction of the neurons within the substantia which causes a decrease in dopamine we'll go over all that but again couple other terminologies so we got Cate lentiform which is the pamin globous patus externus internis thalamus subthalamus and substanti couple other terminologies one is that when we take the CATE and the pamin we actually
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do have a particular name for that and you want to know it's called the striad okay it's called the striatum and the reason why I want you to know these two particular structures connected the CATE and the pamin called the striatum is that dopaminergic neurons which we're going to go over connect to this striatum and whenever there is destruction of the neurons in the substantial nigr Alters the dopamine input on the striatum and that's where you're actually going to see destructive processes in Parkin disease this pathway is called the Nigro strial pathway that's one of the big big Pathways that are altered in patients who have Parkinson's disease okay so we got the anatomy down the next thing we have to do is I want to take this structure here and just kind of zoom in on it so here's our cortex here's the linty form with pamin globous pus externus internis Thalamus and then this is going to be the substantia so this will be I'm going to put a little thing there
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substantia and then we'll have another pathway so there's two Pathways involved here one is called the direct pathway and the other one is called the indirect pathway but again we have the cortex the pamman with the uh the the sorry lentiform nucleus with the pamin globous platus externus internis thalamus this is subthalamus and then again we have our substantia now you're probably wondering why is there two Pathways again if you haven't watched our video on the basil ganglia I'm going to briefly talk about it here the direct pathway is designed Pathway to help to play a role within motor movement particularly desired motor movements if I want to be able to pick up this if I want to actually be able to use this particular marker and perform a particular movement has to be smooth I have to be able to initiate it stop it all of those fine-tuning types of events are modulated or altered via the direct pathway now if I also want to prevent
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any unwanted motor moves like when I bring my pen or my marker into the board from punching it into the board that's actually going to be modulated via the indirect pathway so the basic concept is direct pathway wants to help to initiate motor movements and perform desired motor movements whereas the indirect pathway it's more of 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 actually contract and work I don't want my triceps muscles to be contracting I want them to relax so that I can allow for that movement to occur so it's that type of concept now basic concepts of this pathway is really important from the actual cortex we have particular neurons these cortical neurons and they're actually bringing glutamate down into this area of the pamin as well as the what else the Cod nucleus I got rid of the Cod so I'm just going to represent the pamin but that's representing the
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striatum these neurons from the cortex will come down and release glutamate on particular neurons located within the striatum there's also going to be some neurons located here in the striatum and what happens is these neurons are actually going to be extending from the pamin all the way here to the Globus pitus internis now when the cortex releases I want you to remember that the red is going to represent glutamine okay glutamate is a stimulatory neurotransmitter the blue is going to represent Gaba Gaba is an inhibitory neurotransmitter okay when actual cortical neurons want to generate a movement so let's say that my cortex my motor cortex is like hey I want you to move your arm I have to actually consult my basil ganglia let them know say hey basil ganglia this is the motor movement I want to perform can you make sure that it's smooth it's nice it's not going to be you know I have good motor movement that I want to perform and then prevent
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any unwanted motor movements yeah yeah I got you here's how I'm going to do it so it sends that information down to the pamin and then what does it do it releases glutamate onto this particular neuron what did I say glutamate does what stimulates so it's going to stimulate this particular neuron located in the pamin now from this neuron it's going to extend from the pamin or from the strium all the way to the Globus pitus and turnus and what is it going to release onto the neuron located right here it's going to release Gaba now if I stimulated this neuron it's going to fire when it fires it increases Action potentials down its neuron and releases lots of Gaba onto this neuron now this neuron located in the Globus pus inter internus extends from there to the thalamus to the thalamus but here's what I want you to understand this neuron released glutamate stimulated this one this one's now stimulated he sends Action potentials and releases Gaba Gaba
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does what it inhibits so what would be the actual effect here it would inhibit this particular neuron from firing well then this neuron doesn't fire now what color is it think about it it's blue so what does it release Gaba if it's inhibited is it going to release any Gaba no therefore is it going to be able to inhibit this particular neuron no so now this neuron is released from inhibition and this neuron in the thalamus guess what color it is it's red so it's going to release glutamate and it sends this back up to the actual cortex and releases glutamate here on the cortex to simulate these glutaminergic neurons then they'll go out to the particular skeletal muscle and Trigger that skeletal muscle to initiate a contraction so this is the direct pathway where cortex to the actual striatum stimulates those ggic neurons they're stimulated they release Gaba they inhibit the neurons in the Globus pus Andis if they're inhibited they do not release Gaba if you do not
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release Gaba you don't release an inhibitory neurotransmitter therefore you release these thalamic neurons from inhibition and stimulate them they then release glutamate on the cortical neurons and initiate a motor movement that's how this works now how does the substanti come into this it's very straightforward the substantia has particular neurons that extend here all the way up to these neurons in the pamin or in the stum and it releases dopamine but the dopamine that it releases it on is on a particular receptor here and I'm going to put it here on the side but this receptor is called a D1 receptor now whenever dopamine hits the D1 receptors it stimulates it works via what's called a g stimulatory protein so it increases cyclic a protein kinases and then causes cationic reflux influx sorry and if that's the case what would it do to this neuron it would stimulate it like a son of a gun now this neuron let's make it stimulating stimulating here so you can
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actually see it so it's going to release a lot of dopamine onto these D1 receptors stimulate this neur if it stimulates it on top of the already stimulation from the glutamate you're going to have a heck of a stimulation of this neuron it's now going to release almost no Gaba if it releases almost no Gaba that's going to again sorry if you stimulate this neuron it's going to release lots and lots of Gaba I apologize if you actually stimulate this neuron it's going to release lots and lots and lots of Gaba that's going to inhibit the heck out of this neuron now this neuron is super inhibited it will not release any Gaba if it does not release any Gaba you're going to release this dalic neuron from inhibition intensely and it's going to fire like a son of a gun send action potentials to the cortex stimulate those cortical neurons to go and actually stimulate movement very intensely so what you're seeing here out of the Nigro
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stral pathway is what you're noticing one particular thing which let's actually do it here in Orange you're noticing that this is going to increase motor movement that's the whole concept here you're increasing motor movement now what would it do with the indirect pathway very quickly here you have again cortical neurons same thing they're coming from the cortex they're bringing these neurons all the way down to the pamin or the strium again that's the cad nucleus and the pamin releases glutamate onto these particular neurons here remember glutamate does what stimulates partic it's a stimulatory neurotransmitter so it acts on the same neurons located here in the pamin or the strum here's the difference though in the directed went all the way to the globous pus internis we're going to go an in we're going to go a little bit of a kind of a little detour if you will so now what I'm going to do is I'm going to take this neuron only go here to the
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Globus pus exteris and if I'm releasing glutamat onto this neuron what's it going to do to that neuron here it's going to stimulate it so I'm going to stimulate this particular neuron it's going to fire it's going to release Gaba what does Gaba do inhibits so if I release lots and lots of gabble what's it going to do to this particular neuron it's going to inhibit it where does does this neuron go to subthalamus so now this is going to come down to the subthalamic nucleus on the subthalamic nucleus we have what color here we have these red neurons and guess where they go they go up here to the Globus pitus Andis so you see how we're going to go back to this pathway here we just made a little detour to the subthalamus but let's keep following here glutamate releases on this neuron there's glutamate released onto this neuron and it's actually stimul ated releases Gaba inhibits this neuron if this neuron is inhibited can it release
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Gaba no if it can't release Gaba then what I'm going to do is I'm going to release this substanti sorry subthalamic nucleus from inhibition and therefore I'm going to stimulate it if I stimulate him I'm going to have this release lots of glutamate onto this actual neuron located in the Globus pitus internis so this is going to release lots of glutamate if I release lots of glutamate what's it going to do stimulate this one this neuron then goes the same direction goes to the thalamus and if this is a glutamate stimulating this particular neuron this neuron is a ggic neuron so it's going to release lots of Gaba what's that going to do to this thalamic nucleus it's going to inhibit the thalamic nucleus and if I inhibit that nucleus then I'm going to inhibit the cortical nuclei that go to the actual muscles and this is going to inhibit the the actual motor movement of undesired types of functions so again this glutamate is going to release on uh release glutamate
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onto this ggic neuron in the Globus pus Andis it's going to stimulate him if he's stimulated he releases lots of Gaba if he releases lots of Gaba he inhibits this stalmic neuron this stalmic neuron does not release a lot of glutamate onto the cortex if it doesn't release a lot of glutamate onto the cortex it will not stimulate the cortical neurons enough and they won't initiate the motor movement enough and that could be a good thing for preventing undesired motor movements here's where substantial comes in again we have these neurons that actually extend to the striatum the Nigro stal pathway they release dopamine now normally what you would think and this is where it's kind of like a little wonky sometimes and confusing you would think that our substantia Nigro want generally the whole purpose of the nigral pathways to increase motor movements that's the whole desire increase motor movements but you would think You' want to increase the desired
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movements and then inhibit the undesired movements right that's what you would think now that's what it tries to do but the end result is not effectively the same so we release dopamine onto this actual nucleus here but here's the difference this was a D1 receptor this one is a D2 receptor if it's a D2 receptor that's a g inhibitory Protein that's going to cause potassium on E flux that's going to inhibit that that nucleus so you see how substanti Niger is trying to inhibit the actual inhibitory pathway we don't we want it to inhibit the actual undesired motor movements but when it does that and inhibits this pathway then what do you do think about this keep glutamate the same but have lots of dopamine okay dopamine is going to inhibit this ggic neuron if it inhibits this ggic neuron what is the ggic neuron going to do then is it going to release Gaba no if it does not release Gaba we're going to keep everything black now if it does not release Gaba what is it going to do to
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this neuron it's going to release this neuron from inhibition so it's going to stimulate it if this neuron stimulated he's going to send lots of action potentials down to the subthalamic nucleus releasing lots of Gaba if I release lots of Gaba onto 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 onto this neuron if I don't release a lot of glutamate onto this neuron I don't stimulate him enough therefore he's inhibited if he's inhibited then this neuron doesn't actually go and release a lot of Gaba if I don't release a lot of Gab onto the thalamic neuron I release that neuron from inhibition and I cause this action potentials to increase and therefore I try to stimulate motor movement the whole point that I want you to understand out of this is that the nigral pathway all it wants to do my friends is increase motor movement whether it be on the direct pathway or
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indirect pathway it really wants us to help to be able to perform increasing the intensity of movements imagine a patient has Parkinson's disease now you destroy the substantia nigr neurons if you destroy these neurons what's the overall effect going to be guys that you'll decrease motor movement and that is the problem with this particular disease and sometimes when we decrease this movement it looks at potential ways where 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 Brady kyasia or maybe they're not really moving very much at all and it's hypokinesia or they're not moving at all in general and it could be ainia so these patients can have a lot of difficulty being able to initiate or perform or stop motor movements now here's the other thing that you're probably questioning you're like well yeah I know that they they're slow and they don't move a lot or they don't move
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at all but I they they got this a lot they got the trimmers and their arms are like lead pipes what what's that from I got you there's another potential pathway here that's involved from the cortex there is coleric fibers and these col energic fibers actually go and release acetylcholine onto these Pathways the direct and indirect pathway here's what I want you to remember just flip whatever it does to dopamine whatever dopamine does in the direct pathway acetyl choline does opposite whatever dopamine does in the indirect pathway acetylcholine does opposite so in this pathway dopamine wanted to stimulate the direct pathway what will acetal choline do it'll inhibit it so acetal choline wants to inhibit this particular pathway let's put acetal choline in this one the indirect pathway it does opposite what does dopamine do in this pathway inhibits it so it'll stimulate it so what you notice here is in this particular disease is there's a very
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interesting pathophysiological process let's actually draw our diagram here that in this particular process we have our Cod nucleus this is a good recap I guess we have our lentiform which is made up of the pamin Globus pitus externus internis we have our thi we have our subthalamic nucleus all of these structures here and then we have our substantia what you're going to notice is the B basic pathophys physiological principle in this disease is that there is cortical neurons which are going here and trying to interact there's substantia neurons which are coming here and trying to interact and there is acetylcholine releasing neurons which are going here and trying to interact with this whole basil ganglia whether it be the direct or indirect pathway in Parkinson's disease you have destruction of the substantia igra which does what to the dopamine in that strial pathway so if I were to zoom in on this particular part of the pathway which I will here in a
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second what is the overarching theme here in this disease is that there is a decrease in the dopamine in the striatum there's not enough dopamine release in that striatum on top of that there's also another thing because there is acetal C that's actually inhibiting the direct pathway and stimulating the indirect pathway it's unopposed if there's less dopamine here that's going to lead to an imbalance between the dopamine and the acetylcholine and because of that there's a decrease in the dopamine and then acetylcholine is free to be at higher levels unopposed in the striatum and this imbalance my friends is what leads to other effects of Parkinson's disease particularly the decreased open in the stum is what leads to decreased movement but the increase in the acetylcholine Alters the pathways where that sometimes they're trying to fire at the same time where the direct and indirect pathway are trying to alternately fire at the same time and so
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if you're having your flexors and extensors Contracting at the same time Tremors and rigidity and so because of that in these patients the two particular features in this is that they also have Tremors and rigidity and then associated with this can also be postural instability and that could be a combination of many different things but you get the point here that that's the B basic pathopysiology in this disease so what my approach to Parkinson's medications has to be is I got to figure out a way to increase the dopamine in the strium and decrease the acetylcholine in the stratum to obtain a balance how do I do that let's talk about those drugs let's talk about their mechanism of action and then we'll go over them each in more detail all right so what we need to now talk about is what are those drugs let's talk about the the category of drugs that we can actually utilize that increase dopamine and then those drugs that actually decrease acetylcholine to restore
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balance so with the ones that increase dopamine you can give one particular drug and this is called lopa we'll talk about this one particularly first okay it's one of the most commonly utilized drugs for Parkinson's and basically we'll talk about how that actually gets wor let's actually just kind of list the categories so the first one is elopa the second one is I can give something that actually is really interesting where it's not actually dop because the whole point is to increase dopamine so L dopa will become dopamine what if I give a drug that I don't have to use neurons to make dopamine I just actually allow for it to bind directly to the dopamine receptors so it's like an Agonist if you will so let's talk about that one dopamine
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Agonist okay so we got lopa then we got the dopamine Agonist the next one is okay I can give L Doopa which get converted into dopamine I can give dopamine Agonist which will act like dopamine on The receptors what if I give drugs that actually prevented the breakdown of dopamine and it helped to keep higher amounts of dopamine in the neurons or in the synapses so they can stimulate the dopamine receptors there's less actually getting broken down well there's two particular drug categories here one is called cataco o methyl transf 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 particular drug category to increase dopamine within this Statum is I can give a drug that actually inh increases the synthesis or the release of dopamine from the uh substanti nigr neurons as well as inhibits the reuptake so I have more of it getting released and less of it actually being re-uptake back into
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the neuron so why is that beneficial well if I increase the release and I prevent it from getting taken back up into the neuron I keep more in the synapse to hit the dopamine receptors right so that's the whole concept here and this is called amantadine so this is called amantadine which is its own kind of category if you will so that's how we'll Target those things to increase dopamine to be able to improve movement to increase movement the other situation is I can give drugs to actually decrease the acetylcholine effect for the trimmers the rigidity the postural instability and that's just going to be anti- energic so these are going to be my anti- energic and we will go over these such as Ben tropine and triex vinal a little bit later okay with that being said this is the categories that I want to talk about what I need to do is before we can actually understand each one of these drugs and a little bit more about them I want to have the basic mechanism of
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action so what I really want to do is I want to zoom in on the neurons here in the strium and what I really want to do is I want to focus on the substantia neurons acting on that ggic neuron here in the pamin and then the colonic neurons acting on the ggic neuron and the strum so I just want to zoom in on that and then talk about some of the drugs that actually work in that particular pathway so let's do that here we have our diagram and what we're going to do is we're going to zoom in so this is going to be the substantia neuron so we're going to call this one this is actually going to be the substantia neuron here this is going to be the striatal the striatal neuron so this is the one that was actually located in the pamin and then the CATE nucleus and then this one is going to be the Coler neuron which was being released uh which was coming from the cortex all right so we have an idea here so this is our schema here of understanding how these
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drugs particularly work now when we do that let's actually zoom in here so we know that in order for us to be able to make dopamine release dopamine there's a particular process involved and that's where it's really interesting so one of the things that happens is we have a particular amino acid that actually can get taken up um into uh in across the bloodb brain barrier so this is actually going to be this is representing your blood brain barrier which is this capillary kind of like structure one particular Meo acid can get taken up across the bloodb brain barrier this is called tyrosine now what happens with tyrosine is that tyrosine can actually be worked on by what's called tyrosine hydroxy now when tyrosine is worked on by tyrosine hydroxy it actually gets converted into elopa oh well that sounds familiar I just talked about that drug over there all right cool dopa can then be worked on by another enzyme called dopa decarboxylase and convert into dopamine
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oh well shoot there it is there's dopamine and then dopamine gets put into these vesicles via transporter and then if this neuron is stimulated it generates an action potential the action potential will then move down the axon stimulate these voltage gated calcium channels if these voltage gated calcium channels are stimulated calcium will rush into this particular neuron if calcium rushes into this particular neuron it stimulates the fusion of this vesicle with the membrane which then triggers the exocytosis of dopamine so then dopamine is released when dopamine is released it then can move across the synaptic cliff and bind onto this D1 or D2 receptor depending upon which pathway we're discussing right so that's the concept here now once dopamine exerts its effect here right so it goes it binds onto this particular receptor exerts its effects whether it be via the direct or indirect pathway we know that after dopamine is done then what happens is some of this
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dopamine actually will go via this special transporter and get re-up taken back into this neuron so this is a little a little re let's call this just a dopamine re-uptake transporter okay that's how we're going to abbreviate it now here's the dopamine it gets re-up taken back into the neuron and then from here it can get recycled as we see the dopamine being recycled here back into the vesicle and then be utilized again that's one particular way the other thing is that some of this dopamine may also go via this transporter and when it gets taken up via this transporter it may uh interact with one of these particular enzymes around the mitochondria this enzyme here is very interesting because it does not like it to be recycled it likes to break down the actual dopamine and this enzyme is called the monoamine oxidase B you're like oh wait I feel like I just heard of a drug called the Inhibitors yeah you'll see how they come into play here this actually takes the dopamine and breaks
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the dopamine down and then now this dopamine is an an inactive or kind of like a nonactive metabolite so it has no effect you can't recycle it so we can't reutilize it anymore so you see how giving Inhibitors would prevent that and then we can have more of the dopamine being recycled very interesting right well dopamine is not only broken down inside of the actual neurons via the um monomin oxidase B enzymes it also can be broken down in the periphery like actually I'm sorry within the uh synapse so in the synaptic cleft there's another particular enzyme which can actually break down the dopamine and break it down into like these molecules one of the breakdown molecules it's inactive metabolite as well we we just happen to call this one three OMD and this enzyme here which breaks down the dopamine so it actually can't be recycled it can't be utilized in the synapse anymore this enzyme is called catacol o methyl transferase wait Zach
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you said that there was an inhibitor of that yep guess why because if I inhibit that particular enzyme guess what I'm going to do I'm going to inhibit it from being inactivated into this actual inactive metabolite keep more of the dopamine to either be recycled or keep more of it in the synapse man this is actually making kind of sense is it well we're not done there yet there's another thing here we well actually we'll come to the co energic Neons last here's the other thing here's where we kind of run into a problem so we have particular enzymes out here in the periphery as well so let's say that I wanted to just give dopamine I wanted to give dopamine and if I wanted to give dopamine I give it into the bloodstream what I expect it to eventually get taken up into these neurons and then get utilized you'd think that that would be the perfect situation to just give the patient dopamine problem is dopamine can't cross the bloodb brain barrier
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you want to know how we know that because lopa is the going I told you that's the number one agent that we commonly utilize in patients with Parkinson disease let's say I give the patient l Doopa so I give the patient l Doopa L Doopa has the ability to be taken up into this particular neuron and then again we can bypass the tyrosine and go straight here into this step eventually convert it into dopamine and then utilize that increase dopamine in the synapses right well one of the problems with this is that dopa only a particular percentage of it can actually get taken up into the cross the blood brain barrier and even less of it can be taken down uh taken up if there's a particular process so you know there's another enzymes out here there's an enzyme out here that actually is very interesting and can convert lopa into dopamine I wrote it down over here so this is an enzyme here called tyrosine hydroxy this one's called dopa
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decarboxylase and these stimulate these particular steps so what do you think this enzyme is it's just in the periphery this is called dopa decarboxylase and it likes to stimulate the conversion of peripheral lopa into dopamine guess what dopamine can't be taken up into the actual across the blood brain barrier so I can't utilize that so I have to give a drug which we'll talk about a little bit later to actually inhibit the dopa DEC carboxilate to prevent it from getting converted into dopamine so that it's pretty much all lopa so that it can be taken across this actual uh blood brain barrier and we'll talk about a little bit later but here we already know that lopa can get taken up here's another problem not only is this enzyme potentially causing do lopa to get converted into dopamine meaning less lopa gets taken out but there's another drug or another enzyme and this other enzyme actually can convert lopa into what's called um
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so this one's actually called 3 Mt apologize this one is called 3D now you're already kind of get an idea here this was a CT that converted this into 3mt so dopamine into 3mt this is going to convert lopa into 3D and this drug is called CT so CT also converts alopa into this inactive metabolite it's an inactive metabolite just called 3D now 3D is also not able to be taken up across the bloodb brain barrier so we can also give drugs now here's the interesting thing we give drugs that can inhibit the CT enzyme out here in the periphery to make sure more elopa gets taken up and if we have that drug that also can penetrate across the blood brain barrier guess what else that CT inhibitor can do inhibit the central one to make sure that more dopamine is present in the synapses as well and there is one of those drugs and we'll talk about it's called topone interpone is the is the one that actually only does particularly the the periphery one um but here that's
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the whole concept I really want you guys to understand is that lopa is one of of those primary drugs that can actually get taken up into the neurons and get used to convert into dopamine we can actually prevent lopa from being taken up if it's acted on by the dopa decarbox ASE and converted into dopamine this one can't be taken up so now I have no ability to be able to get the lopa across or the dopamine across on top of that if lopa is acted on by the comt gets converted into an an anactive metabolite that also can't be taken up again that prevents lopa from getting taken up we'll go over all of this process when we talk about levodopa by itself but that's one of the drugs that's how I get alopa to actually be one of the drugs because it can actually get taken up utilized in this Pathway to make dopamine the other one I said was the dopamine Agonist what if I gave a particular drug here that actually works specifically right here so I actually have it cross the blood brain barrier
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but this particular drug dopamine Agonist if you will I can actually have this drug come and bind specifically right here if it binds to that actual receptor I can exert the same exact effect as dop on that one this would be The Agonist this is your dopamine Agonist okay and we'll go over the different drugs there but that's the dopamine agus so we already see how we can utilize L Doopa so here I'm going to actually put l Doopa just so we can recognize that this is the first drug that we can actually give L Doopa and we see how it can actually be utilized it can be taken across the bloodb brain barrier and then utilized in this Pathway to make more dopamine right we can make more dopamine and release more dopamine within the synapse so there's drug one there's drug two the next one we said is the Inhibitors the CT Inhibitors and the maob Inhibitors if I gave a particular drug like a c Mt inhibitor it's going to inhibit this particular enzyme if I inhibit this
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particular enzyme I'm not going to perform this particular pathway so I'm going to inhibit the conversion of dopamine into this inactive metabolite and therefore I'm going to allow for more dopamine to be present within the synapse stimulating these particular receptors in the same situation if I give a drug called a monoamine oxidase B inhibitor it's going to inhibit this particular enzyme if I inhibit this enzyme I'm not going to allow for the dopamine that gets re-uptake or the dopamine that's present in the actual uh uh axon bulb to get broken down so I inhibit it being converted into an inactive metabolite and I allow for more of the dop to be present here in the synaptic bulb so now more dopamine is going to be released in the synapse because I'm going to have more of it being recycled and in these vesicles that means more dopamine can bu onto these dopamine receptors pretty cool right the last one is a manine now amantadine really does a couple
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different things a manine Works to stimulate the release so you see this process where the actual vesicles Fus with the the cell membrane it increases that particular pathway so once to increase the synaptic vesicle fusion with the actual uh this the synaptic vesicle with the actual membrane and therefore we increase the dopamine release into the synapse that's one particular mechanism the second mechanism is it also is going to inhibit the dopamine reuptake Transporters because if I inhibit these dopamine reuptake Transporters I don't actually allow for Le I don't I'm not going to allow for as much of it to come into the vesicle which may sound like a bad thing thing but remember if I bring it into the vesicle I can recycle it but I also increase the chance of it being metabolized if I want more dopamine in the synapses what if I just inhibit this transporter so now all this dopamine that's actually was supposed to be in the actual synaptic Clift it gets
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re-uptake right it's there's less of it here but if I inhibit this transporter now this dopamine will not get taken back up and if the dopamine will not get taken back up then more of it is actually going to stay in the synapse and hit more of the dopamine receptors so that's the concept of these drugs for increasing dopamine either give L Doopa and it'll eventually get converted into dopamine you just have to be careful because it can get broken down into dopamine in the periphery by dopa decarboxylases or into an inactive metabolite via comt so we'll talk about those a little bit later we can give dopamine Agonist that directly stimulate the receptors we can give drugs that prevent the breakdown of dopamine like maob Inhibitors and CT Inhibitors and we can give a drug that stimulates the synthesis or release of dopamine and inhibits the reuptake to keep more of dopamine in the synapse the last situation here is the anticholinergics it's not too hard here we have
37:38
muscarinic receptors and there's so many different types of muscarinic receptors here present but I'm just going to put down here that we're going to have muscarinic receptors and we're not going to go through all the different types there's five different types of muscarinic receptors right so because you have these muscarinic receptors when acetylcholine gets released from these coleric neurons it binds on to this particular music receptor and depending upon if it's in the direct pathway the indirect pathway we we already know the kind of effect that it'll have if I give a particular drug category here like anticholinergics what the anticholinergics are going to do is they're going to inhibit this interaction they're going to inhibit this particular interaction so here I want to give anti- Cola nergic because they will inhibit the acetylcholine from being able to exert its effect on the striatal neuron preventing that excessively High acetylcholine release so you see now the
38:37
mechanism of action of these drugs it's actually really cool so now what I want to do is I want to go over each one of these drugs I want to talk about L Doopa a little bit more I want to go over dopamine Agonist a little bit more I want to go over these Inhibitors and then amantadine and then lastly we'll talk about the anticholinergics all right so when we first talk about um these drugs of increasing dopamine in the stratum we're going to talk about lopa first we already have the understanding of their mechanism of action but I think the nice thing is kind of recapping this again just again space repetition is important to kind of keep going over these things but the basic concept is that when you give a patient lopa right you're going to give it to them orally when it's given orally it crosses the GI tract when it cross the GI tract it gets into the bloodstream so here lopa is now in the bloodstream now when the lopa is in the bloodstream we already talked about how
39:20
there's two particular Pathways here one is we can send lopa into what's called 3 OMD and this was done via the CT enzymes right we also can send lopa into dopamine which again neither of these can cross the bloodb brain barrier and that was coordinated via the dopa DEC carboxilate the whole goal though is to get as much lopa as possible into the actual synapse in this area here to cross the blood brain barrier because again we remember that we talked about how we have tyrosine and then tyrosine is converted into lopa via tyrosine hydroxy and then lopa is converted into dopamine via dopa decarbox taken up into the Transporters if there's an action potential so calcium comes in stimulates the vesicles to fuse and then they release dopamine and then dopamine gets out here binds onto the D1 or D2 receptor and then acts on this particular stral neuron we we already know all this right but what's important to remember is that L Doopa right whenever you think about this drug
40:30
the big things that I really want you guys to remember here with L Doopa is that L Doopa is really important because one of the big things is that this is going to be your first line drug it's your first line drug now preferably some of the literature will actually say that you should actually go with this one first if the patient is greater than 65 years of age or if they're less than 65 you can actually use dopamine Agonist instead again I just want you to remember it's first line drug if you want to also remember that on top of that it's particularly first line and those greater than 65 years of age but it is going to be your first line drug now here's the big thing because lopa has difficulty in being able to get across the bloodb brain barrier because some of it can actually be converted to dopamine we should often times give lopa with Carbidopa so lopa and Carbidopa are often given together now you're probably wondering where the heck do carped Doopa come into
41:28
play I already have the L Doopa I understand how L Doopa is involved here because it's going to work here to increase or stimulate the increase in lopa we already know that where's the Carbidopa come into play Carbidopa inhibits the dopa decarbox enzyme so here I have carb dopa and Carbidopa Works to inhibit the dopa decarboxylase if I inhibit the dop dopa DEC carboxilate I inhibit the conversion of L DOA into dopamine so less of this pathway is occurring and then I have more of the lopa available to cross the bloodb brain barrier more do alopa gets across you make more dopamine you release more dopamine into the synapses and stimulate more of the dopamine receptors bab boom all right so you see the point here is that Carbidopa if given in combination with L Doopa will make sure more L Doopa crosses the bloodb brain burrier because it inhibits dopa DEC carboxilate the peripheral deopa decarbox okay and that's also
42:32
important because the other beautiful thing about Carbidopa is it reduces the amount of dopamine in the periphery because guess what all this dopamine all right all this dopamine has the ability to produce adverse drug reactions so if I give carbid dopa I prevent more I prevent less dopamine from being in the periphery and so Carbidopa effectively will reduce Carbidopa will effectively inhibit a lot of these adverse drug reactions associated with the high amounts of dopamine that's being converted in the periphery Isn't that cool all right so we have an understanding here lopa first line agent really to be given impatients with parking disease if you really want to sometimes you can wait until they get at least greater than or equal to 65 years of age it might be more preferred but it's a first line agent and you have to give it with Carbidopa because it inhibits the dopa DEC carboxilate prevents it from getting converted into dopamine dopamine can't cross the blood
43:29
brain barrier so you get two effects out of that one is you make sure that you have more L Doopa to cross the blood brain barrier and be utilized and you have less dopamine in the periphery to cause adverse drug reactions now with that being said what are some of the adverse drug reactions that you can see well one is that if there is a lot of this dopamine present dopamine has a very profound cardiac stimulation so I want you to think about pretty much elevated dopamine is really the problem here so elevated dopamine what it can do is it can really stimulate the heck out of the uh SA node and AV noal system so it might make it fire a lot more and if it makes it fire a lot more you're going to see a very profound increase in the patient's heart rate so you're going to watch out for tacac cardias or tach arhythmia in these patients the other thing is that there's dopamine receptors that are very profoundly um found on veins which is really interesting right so there's lots
44:25
of dopamine especially D2 recept that are present on our veins and what happens is when dopamine binds onto these particular receptors it causes vasod dilation so Vaso dilates if you vasod dilate you decrease the systemic vascular resistance or actually I would actually more specifically not systemic vascular resistance you do decrease resistance but you don't squeeze the vein if I don't squeeze the vein I don't squeeze as much blood into the heart so I reduce my Venus return that reduce uces the stroke volume and that can actually cause the patient to develop orthostasis because whenever they have a they go from a one position to another they don't have adequate Venus return and because of that this can lead to orthostasis so whenever the patient stands up or goes from a seated to a standing position it can stimulate this orthostatic mechanism because it vasodilates the veins very profoundly okay via the D2 receptors and then also
45:24
there's dopamine and beta receptors that are present on the cardiac uh system particularly the nodal system and they may see a tacky arhythmia associated with that so watch out for tacac cardia and watch out for postural hypotension or orthostatic hypotension the other thing lots of dopamine is also interesting because when you have lots of dopamine there's particular things that you want to remember that there's a lot of different dopaminergic Pathways besides the nigr strial pathway right so here's our uh Nigro stal pathway that we already talked about going from here to the basil ganglia we also have um Pathways that can actually go and connect to the lyic system so here I'm just going to draw these here in like green this is just going to be my lyic nuclei and this could be a lot of different structures the amydala the hypothalamus the mammilary bodies there's so many different structures but this is called the misol limic pathway
46:16
right so you have something called the Miso limbic pathway and this is a pathway that's associated with your emotions your reward your thought process a lot of those things so because there's lots of dopamine that's being released within the misol limic pathway that can cause a lot of like actual emotional issues and so some of the things that you can see because of this is you can start seeing very nasty types of effects here it can start off with the patient has like anxiety and then it can actually Bridge pretty significantly and it can move to things like delirium it can move to things such as um hallucinations delusions which is terrible and then even progress all the way into like psychosis so because of that that's kind of a scary thing to think about here is that you really want to watch out here for nasty adverse effects via the Miso limic pathway when there's lots of dopamine released within this pathway between the um substantia and also
47:19
all the way connections into like the limbic nuclear like the amydala like the hypothalamus like the mammary bodies like the singulate gyrus all of these different structures here it can lead to increases in anxiety delirium hallucination psychosis even sometimes impulse control so watch out also for impulse control and impulse control some like gambling not even kidding sometimes it can just cause a lot of like loss of inhibition so these are big things to think about with this there's one more interesting thing you know there's a there's a a center here located within the medulla uh let's draw this one here 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 chemo trigger zone now the chemo trigger Zone has lots and lots of dopamine receptors present on it and so we can actually use particular drugs to actually block those dopamine receptors
48:13
when people are feeling like kind of nauseous or vomiting but if you have lots and lots of dopamine that's lots of dopamine binding onto these chemo trigger Zone receptors the dop receptors is present on the chemo trigger Zone which guess what that's going to do if you stimulate the chemot trigger zone or the Center that's going to cause these patients you're stimulating the edic center this will trigger nausea and vomiting so another particular thing to watch out for in these patients is another adverse effect here is nausea and vomiting due to lots of dopamine stimulating the chemot trigger Zone leading to the activation of the TIC Center in the medulla leading to nausea and vomiting all right so we now know that increasing dopamine can cause cardiac stimulation postural hypotension can stimulate the misol limic pathway causing a lot of like psychotic or uh you know delirium type of effects and cause a lot of nausea and vomiting via the edic center in the medulla you know
49:03
the interesting thing is a lot of these drugs that are increasing dopamine in the strium whether it be decreasing its you know uh breakdown whether it be acting like a dopamine Agonist whether it be whatever all of the drugs that we talked about that increase dopamine guess what all of them can have these types of effects which is important to remember the next things that I want to talk about here is the effect of that there's way too much dopamine because they give way too Hefty of a dose or maybe because you're having a patient who's taking do uh levodopa and Carbidopa with another drug that just increases too much of the dopamine in the synapsis either way there's just way too much dopamine present in the striatum what's another negative side effect because generally can increase movement what if it increases movement way too much let's talk about that all right so we already talked about all of these Pathways here but the basic concept here is that we had again the
49:52
nigral pathway which is the dopaminergic pathway from the substantia connecting to the neurons in the pamin or the strial area right and we already know that there was particular neurons here that we already discussed that it could go in two Pathways one it could be the direct pathway right the other is it could go via the indirect
50:16
pathway and the whole concept here is the
50:22
same that whether it be the direct or indirect pathway in this situation what we know is is that dopamine Works to be able to if it's the D1 receptor to stimulate the direct pathway or if it's the D2 receptor to inhibit the indirect pathway we know the overarching theme that we already talked about above is that it does what it increases movement right that's the whole concept and that's the whole beauty of this and that whenever you are increasing movement that's supposed to help patients who aren't really moving a lot at all but what if you give way too much of a dose way too much so there's just way too much dopamine whether this be such a high dose of carbid dopa Le aopa whether this because you're giving L Doopa and something else that's increasing dopamine in the synapse like you give it with a comt inhibitor you give it with an M Mao B inhibitor you give it with a dopamine Agonist you give it with a manine all of those things are
51:16
going to bring too much dopamine into the strium so all in this area here there's just way too much dopamine that's going to increase the firing way too much and so now you get an abnormal increase in movement to the point where it's actually pathological you'd think it'd be beautiful but no this is a problem and whenever the movements are so intense we call this dis kyasia and what could this look like there's so many different ways that it can look like some of the things that you want to think about here is that sometimes the patients can exhibit things like Korea so they have just like this unorganized type of movement where they can't control it or they have things like athetosis so they have kind of like a a snake like movement of their their fingers um they can't sit still so they have aysia they're super Restless these are potential things that we're seeing because you're causing way too much stimulation of the indirect pathway and
52:12
a lot of the extra pyramidal symptoms are starting to develop so watch out for this this is one of the things that you can see really with high levels of doping whether it because you give too much lopa or whether it be uh lopa plus something else that increases the dopamine in the synapse like a dopamine Agonist or a CT inhibitor or an maob inhibitor you get the point it's one of those potential Concepts that you're seeing here all right my friends so we have dyasia as another potential effect there's one more thing that I want to talk about it's actually really important that you may see on your exams whenever patients are given dopa we can they can experience something called the onoff phenomenon and and is very straightforward the concept behind this is that if you think about it um patients who have Parkinson's disease right so let's say here we have just a small quick diagram here as you think about this here's our substanti Niger right there's neurons are supposed to go
53:16
and connect to the strium right that's the whole concept as you have Parkinson's disease progressing and progressing and progressing what happens to the number of substanti neurons the decrease so as the disease continues to progress there is a decrease in the number of substantia neurons which means that there's less neurons available for dopamine use so not only does it mean less dopamine but that means even if you give a drug like elopa if there's less neurons you don't have the nerve terminals to use cuz remember what does lopa need it needs the terminal to actually get into get converted into dopamine get put into the synaptic vesicles the neuron to be stimulated then to release it so that's a problem even though I give patients elopa I need a certain number of neurons present to actually utilize the lopa to make dopamine do you understand what I'm saying so because of that what we start seeing is is we see this effect where let's say that I give the patient the
54:24
drug I give them lopa carb Opa they take the drug they see a particular effect of the drug for so many hours then the drug starts wearing off and then what happens their symptoms come back so you give them another part of the drug right as the neurons start becoming destroyed and destroyed and destroyed you have less dop energic neurons available for lopa so these symptoms start actually developing a lot quicker and so patients will take the drug they'll have this period where they're on right so they're having good Improvement and Mobility they're doing everything they're moving well but then the drug starts actually wearing off very quickly and they go into this off phase so then they have ayia where they're not moving at all and they're at risk for like pneumonia aspiration dvts all that stuff or they're just moving very very slow so they're going back they're kind of res resulting back in their Parkinson's phase and so what do you have to do then
55:15
you have to either give a higher dose but what's the problem with that so think about that all right here's our dose response curve right so here is my maximum efficacy my emac right you guys remember this from the pharmacodynamics lecture in Parkinson's disease what we see with the off phase where it happens is we see there is a decreased number of substantial neurons meaning there's less neurons available for dopamine even if we kept the dose the same in this patient when they're in the off phase they're wearing out okay the drugs wearing out what we notice is even at the same dose we notice a decrease in the emac look at the emac now the emac has decreased so in this situation here we notice a decrease in the efficacy of the drug there is a decrease in the efficacy of the drug and the reason there is a decrease in the efficacy of the drug is because the number of neurons are decreasing and they don't have enough neurons available to be able to use the alopa to make
56:15
dopamine so what would you think ah well what I could do is if I increase the dose that would work right so let me go ahead here and just jack up the dose so now here on the x- axis is the dose on y- axis is the response the response is dependent upon the lopa the dose of lopa but it's also dependent upon the number of neurons that's what we got to remember I can't change this but I can change the dose and so you think oh here we go here's what I'll do I'll increase the dose and if I increase the dose as I go this way maybe I'll get to that maximum efficacy but if you guys remember from our pharmacodynamics lecture yeah we may get to that Max efficacy but as I start working farther and farther and farther down this dose range what do I increase the risk of I increase the risk of these toxic doses so now I start getting into the the realm of negative side effects because as I increase the dose of my elopa I'm going to see more of the
57:14
dopamine in these synapses I'm going to see more of the dopamine effect on the heart I'm going to have more of that dopamine in the misol liic pathway more of the dopamine see more dynesius so as I increase the dose I'm going to see increase in the toxic adverse drug reactions so I can't increase the dose too much I may be able to increase it a little bit but what could I do instead to keep the dose the same so I'm not having so much l Doopa getting converted into dopamine what if I keep the dose the exact same but I give it more frequently right so in patients who have What's called the onoff phenomenon so let's actually write this here the on off phenomenon which is basically on is when the drug is working it's working in those actual synapses it's getting taken up by the neurons it's working to be able to improve their symptoms then as the drug wears off which can start occurring really really quickly as the number of neurons are becoming less this
58:12
off phase will come on very very quick so the drug won't last very long and so because that you think oh well the ethic is decreasing if I increase my dose I'll increase the efficacy yes you will but then you end up with toxic adverse drug reactions so the ways that I prevent the off phase preventing the drug from wearing off quickly is I could do a couple things one one option here is I in uh I I decrease the time intervals so instead of me giving it I'm just making it up every 3 hours I'm sorry every uh six hours I give it every three hours so I increase the frequency of the drug dosage here's one other option another option is maybe I give this drug lopa in combination with something else that prevents its breakdown or acts like it it just doesn't cause as much lopa to convert it into dopamine so I give something else besides lopa oh that's a great idea so let me give lopa plus something that will not actually cause lopa to get converted into dopamine so anything else
59:23
anything I can give away the dopamine Agonist I can give it with a CT inhibitor I can give it with an maob inhibitor you get the point here I can give L Doopa and Carbidopa with any of the other dopaminergic drugs because what that's going to do is is it's going to help to be able to either increase dopamine in the synapsis or have a drug that acts just like dopamine without having the toxic adverse effects of dopamine do you understand that point that's the benefit of this so to reduce the off phase in the onoff phenomenon as number of neurons of the substantial nagra are dying you have less synapses available for Less dopamine you would think if I increase the dose I'll work it will but it give you toxic adrs so what do I do decrease the time interval and keep the dose the same or give elopa and a combination of another dopaminergic drug such as dopic dopamine agonis CMT Inhibitors maob Inhibitors and I couldn't fit it in here but also
1:00:22
amantadine all right my friends so now let's kind of blast through this DOP mean Agonist right so we already covered L Doopa and Carbidopa thank goodness it's not hard names dopi agones let's blast through this all right we have here that we know that tying can be taken up into this neuron tying can then be converted into lopa then it can be converted into dopamine and then dopamine can then be taken up into this vesicle can be stimulated via calcium cause it to fuse with the cell membrane when it fuses it releases dopamine out here into the synaptic CFT which then binds on to the D1 or D2 receptors of the strial neuron we know these things what if I gave a drug that didn't have to go through this pathway what if I gave a drug right like a dopamine Agonist which had the ability here it is to cross the blood brain barrier and then directly go here and stimulate this dopamine receptor just like dopamine could wouldn't that be awesome and I can produce the same exact
1:01:21
effect theoretically yes so what are some of these dopamine a Agonist that you ask okay some of these dopamine agonists that I really want you guys to know so there's two different categories if you will one is called the OTS and these ones have a lot of like nasty side effects that we'll discuss um but there's two particular ones here and we don't really utilize these anymore one is called actually we're just going to write down one because one actually we don't even use at all so it's really just bromocryptine so bromo crype it's not really utilized anymore for patients with Parkinson's disease okay there is another group of dopamine Agonist which are called your non ergots and these have less of the actual toxic side effects that bromocryptine has um and this would be there's two particular ones that I want you to know premy paxel and the other one is called renol renol now these two particular drugs U again your non ergots prol and rinol are actually going to be interesting drugs
1:02:22
that we can actually utilize in patients potentially you can even consider this a firstline agent and patients less than 65 years of age so remember I said levodopa technically First Line agent more particularly in those greater than 65 we can actually utilize this is an actual alternative to lopa Carbidopa and patients less than 65 years of age so we can actually utilize this let's actually write this one down it can be considered a first line in patients less than 65 years of age which is interesting now when we give these drugs we know that they stimulate the dopamine receptor so they'll produce the exact same effect on the direct pathway and indirect pathway improve movement that's all these drugs are going to do so levodopa Carbidopa remember all of the do drugs there are just trying to improve initiating movement they're improving brainia hypokinesia ainia Etc they're not really working too much for the trimmers and the rigidity that's going to be your anticholinergics one of
1:03:14
the big things to think about with these particular drugs is that again they do increase dopamine in the central nervous system okay so because they do increase dopamine in the central nervous system you can see some of the similar effects that we talked about with lopa and what could that be well let's just write it down here if it acts here on your misol limic pathway if it works on the Miso limic pathway what are we going to see we're going to see all of those uh behavioral effects so one of the things that we could potentially see here is the behavioral changes behavioral changes and this was due to what pathway the misol liic pathway so you're incre seen the dopamine in the misol limic pathway we could also see what else we can also see what other adverse effect here we can see the emesis right so we can see nausea and vomiting and this is via the what pathway here if I were to draw out here another a little very plump diagram here we're going to have
1:04:14
the medulla what was that structure that I drew down here in the medulla the chemot trigger zone so this could be due to the stimulation of the edic center within the medulla or the chemot trigger Zone okay so you get the point here so you're stimulating the me olymic pathway or you're stimulating the edic center with the medulla chemot trigger Zone causing nausea vomiting so you get the same effects that you would with aloba you just don't get as much of the cardiovascular effect such as postol hypotension and the tachio cardiio because you're not going to have as much of that dopamine in the central nerve sorry in the periphery now the next thing here is that you can also have a very interesting thing but you we see this particularly more with the Urgot so the ergots and ergots you can both see these effects of the central nervous system effects via the mimic pathway via the edic center and the medulla you see may see a mild degree of um postural hypotension you may see a very mild
1:05:07
degree of tacac cardiio but not as much in comparison to levodopa Carbidopa so with these things with the ergots you can also see two other particular effects that I want you guys to remember it can actually cause a lot of fibrosis of the cardiac tissue and the lung tissue and so because you may see a degree of fibrosis and vasospasm so fibrosis and vasospasm of the uh particular structures present within the lungs and in the cardiac tissue so watch out for that as well so we got dopamine Agonist again Urgot bromocryptine non- ergots perip paol and renol this is the particular first line agents that we utilize we don't use Urgot because of the pulmonary and cardiac fibrosis retrop peronal fibrosis they also cause but these can be first line less than 65 years of age and again just watch out because it has the similar side effects as lopa does as well all right let's come down to the next two drug categories which are being uh preventing the degradation of dopamine right via
1:06:04
particular mechanisms such as the comt Inhibitors or the maob Inhibitors so same concept here guys ready so we have here again same concept you have lopa or tyrosine whatever it may be this is getting taken up right so we have tyrosine this can get converted into lopa and then dopa gets converted into dopamine this can get taken up into the vesicles calcium enters in stimulates these vesicles to fuse with the cell membrane releases the dopamine out into the synapse dopamine binds onto the D1 D2 receptors and then again acts on these stral neurons to produce the effect on the direct and indirect pathway improving movement right now with this being said we know that the dopamine right that's out here in the synapse son of a gun it can also try to get reup taken right so it can be reup taken via the reup take Transporters but we also said that it can actually be broken down and turned into an inactive metabolite called 3mt so this is an inactive metabolite this
1:07:04
is performed via an enzyme called CT catle ome methyl transferase now I also told you that lopa is also interesting because in the actual periphery not across so here's the blood brain barrier so we have an enzyme a CT enzyme in the central nervous system and we also have a comt enzyme out here because remember I told you that alopa can get converted into what's called 3D and this was via the CT enzyme so there's two of these enzymes one in the periphery and one in the central portion now what I want you to know here is that when we give these particular drugs the CT Inhibitors what we're doing is we're inhibiting these particular enzymes as we talked about before so we're inhibiting this and allowing for more lopa to be present to cross the bloodb brain barrier make more dopamine increase dopam in the synapse right that's one way the other way is we're inhibiting it from being broken down so we're inhibiting this pathway and allowing for Less dopamine to be broken
1:08:04
down and increasing the amount in the synapse stimulating the heck out of these dopamine receptors last thing here when we talk about these particular drugs the CMT Inhibitors it's important to remember that there is particular drugs that are going to inhibit the central CTS and then ones that actually inhibit the peripheral CS what do the what does it mean with the c c Inhibitors that actually inhibit the Central CT enzyme you guys know this is called tol Capone so tol Capone is going to be one of those particular drugs that inhibits the central comt so it helps to be able to increase the dopamine present within the synapses right but you know what else is interesting tol Capone also inhibits the peripheral one as well so we have tol Capone and another drug here called int Capone and these inhibit the peripheral Co T and that allows for more lopa to cross the actual bloodb brain barrier get into the actual Adin getting into these actual do energic neurons to be
1:09:04
converted to dopamine and release more dopamine into the synapsis so either way what you're noticing here is that tol Capone can increase the actual dopamine present within the synapsis only problem is though with tol Capone is this is superiorly hepatotoxic so tol Capone is extremely hepatotoxic okay so it is extremely hepat toxic extremely so because of that you see this way more specifically with tol Capone we don't often use this drug for that reason so therefore the only true option that we actually commonly go to is in Capone just because of the nasty adverse effects that tolcapone has on the liver so because of that in Capone really the only job that it would do is increase Le Adoba uptake right and increase the amount of dopamine in the actual synaptic neurons to have allow for more L Doopa to be present within the actual synaptic Clift if you were able to give toone yes you would increase dopamine within this the actual synaptic Clift as well so because of
1:10:08
that often times the true indication for these particular drugs is they are an adjunct they are an adjunct to alopa and Carbidopa and really the only utilization of these drugs is they commonly given in the onoff phenomenon so whenever those patients are in that off phase and we don't want to increase the drug of alopa or we've already decreased the time intervals and given it more frequently and we're at that point where we need some more effect because the patient is still having hypokinesia ainia dyasia then what we can do is we can add that on to the levodopa Carbidopa and give that in combo to either allow for more elopa to get taken across the actual blood brain barrier as well as increase the amount of dopamine present within the synaptic CFT that's the concept here now because these do help to be able to increase dopamine guess what you're going to see for these the same adverse effects that you'd see with the lopa or the dopamine
1:11:10
Agonist so adverse effects that you want to watch out for here is definitely hepatotoxicity with topone but also watch out for again the nausea vomiting from the stimulation of the Ematic Center in the medulla and behavioral changes from the uh potential changes in misol limic pathway so behavioral changes and again that's also other things that you want to think about with these particular drugs all right that covers the CMT Inhibitors let's now move on to the next one which is the mob Inhibitors all right my friends so now mob Inhibitors so it's the same concept here we're trying to inhibit the breakdown of dopamine that's the whole concept to increase dopamine present within the synapses or recycle more dopamine whatever it may be so we talked about CMT Inhibitors right we talked about how they either enhance L Doopa across the B brain barrier uh uptake or how they help to be able to prevent the dopamine breakdown in the synaptic CFT right toone andone with these drugs it
1:12:02
may OB Inhibitors right because you know there's actually two different types of monomin oxidases there's monomin oxidase a and monomin oxidase B we'll talk about that because potentially the adverse effects we may see from these drugs as well but basic concept here man this is going to be burning you guys' brain already so lopa gets taken across when it gets taken across the blood brain barrier we know that we have tyrosine and that tyrosine can get taken up into converted into lopa LD Doopa can then get converted into dopamine and then dopamine can be taken up into these vesicles if calcium ions come in when calcium ions come in they stimulate these actual vesicles to fuse with the cell membrane when they fuse with the cell membrane they release dopamine into the synaptic CFT dopamine then binds on to the dopamine 1 dopamine 2 receptors and stimulates this potential strial neuron or inhibits the stal neuron now we know this particular concept here now
1:12:53
here's the other thing remember I told you that dopamine can actually be broken down so sometimes what can happen is dopamine may be actually when it's done working right dopamine can be taken up via reuptake Transporters all right so it can may be taken up via reuptake Transporters here we can actually use this potentially over here we have our blue transporter over here so let's actually use that side but here we know that when dopamine is done exerting its particular effect here we know that dopamine can be taken up via these dopamine reuptake transporter we just abbreviate in that way now once the dopamine is inside we know that it can actually be taken up into the vesicles and potentially reutilized the same concept whether the dopamine was re-uptake or whether the dopamine is present within this area of the actual axon terminal bow because it's being synthesized what can happen is the dopamine can be acted on Via these enzymes present on the outer membrane of the
1:13:48
mitochondria and these enzymes are called the monoamine oxidase B enzymes so monoamine oxidase B enzymes and what they do is they take the dopamine that's either being recycled or the dopamine that's being synthesized regardless and then break it down they actually convert it into an inactive metabolite and effectively that means that you're having less dopamine that can be recycled and taken into this vesicle or less dopamine that's being synthesized being taken into this vesicle either way it's reducing the amount of dopamine that's present within the synapse to act on these neurons so if I give a particular like an maob inhibitor what these maob Inhibitors are doing is these drugs are inhibiting this particular enzyme if this maob inhibitor inhibits this particular enzyme it will not allow for it to take dopamine and convert it into an inactive metabolite so therefore more of the dopamine that's either being synthesized or recycled is going into
1:14:48
the synaptic vesicle and more dopamine is being released into the synaptic CFT acting on the striatal neurons you get the point here we're increasing the actual amount of dopamine available in the synapsis by preventing its breakdown what are the different drugs that are a part of this particular category so there's two particular drugs that are maob Inhibitors one is called celene celene and the other one is called radeline these are the two particular drugs that I want you guys to remember that are mov Inhibitors now often times when we give these particular drugs they're not really firstline agents we don't even really give them very much anymore but one thing to remember with these particular drugs is that they are often an adjunct they're an adjunct to levadopa and Carbidopa again often times in the on off phenomenon because again it's just going to help to be able to allow for more dopamine to be present within the synapses by preventing its breakdown
1:15:55
sometimes you can and this is again textbook answer you can use it in the less severe cases the more mild cases of Parkinson's disease but often times again we just don't usually prescribe this as a very common monotherapy agent so again big thing to remember it's usually often times an adjunct to levodopa and Carbidopa in true textbook Literature answer you can use it in the very mild cases of Parkinson's disase but often times it's not really a monotherapy agent all right so that's the big things to remember for this drug now when we we talk about celene and radeline usually as an adjunct to levodopa Carbidopa to prevent the off phenomenon or the off effects of the onoff phenomenon things that we can also think about this is the adverse effects this is where I told you there's two particular enzymes so on this um I'm going to draw this here in blue here this is going to be one particular enzyme that's present on the uh mitochondria and this is going to be
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called the monoamine oxidase a enzyme and then over here in red we're going to have the other one here which is called the monoamine oxidase B and we already know what the monoamine oxidase B does right we know that it basically takes the dopamine that's present in these vesicles and then inhibits it into converts it into an inactive metabolite the monoamine oxidase a basically it's responsible for breaking down things like norepinephrine epinephrine and five hydroxy tryptamine which is serotonin so it's basically responsible break breaking these down into inactive metabolites so if I give a monoamine oxidase B inhibitor what's important to remember is is that they're very selective so they will inhibit the monoamine oxidase B they'll inhibit the dopamine from being broken down and so they'll effectively try to increase the dopamine in the central nervous system so adverse effects that you would see here is what all the things that we
1:17:47
talked about the increaseed dopamine in the CNS so we already talked about this that the adverse effects of this would be nausea vomiting due to the emedic Centum stimul ation or it could be due to the behavioral changes via the work in the what situation the misic pathway one other thing at very high doses these monomin oxidase B Inhibitors lose their selectivity so at very high doses you can of the monomin oxidase B you can inhibit the monomin oxid a a so this is very high doses of monoamine oxid B Inhibitors very high doses because they're very selective when that happens you inhibit these enzymes they don't break down norepinephrine epinephrine five hydroxy tryptamine oh my gosh could you imagine the disaster with this this can lead to two potential things one is if you have massive amounts of norepinephrine epinephrine circulating through your bloodstream oh my gosh hypertension Galore so you're going to see a hypertensive crisis as as a result
1:18:50
of this especially if the patient takes this with tyramine so remember can also be really exacerbated if taken with tyramine or some other agent okay so some other particular some other potential drug but generally tyramine is that common example that they use in the boards it also can increase your serotonin levels and so because of that it may lead to something called serotonin syndrome and again you see this usually in combination with like a tricyclic anti-depressant or an SSRI or something else in combination with this image o inhibitor but you get the point the point is that often times these maob Inhibitors they really cause the similar side effects of lopa just potentially within the central nervous system because again what they're doing is they're increasing dopamine in the synaptic Cliffs that means in the synaptic cffs of the edic center in the medulla the synaptic cffs in the molic pathway but at high doses it has lost its selectivity inhibits The Mao a
1:19:50
Inhibitors increasing norepinephrine and serotonin leading to hypertensive pces especially if taken with tyramine or serotonin syndrome especially if they take the M inhibitor with a tricyclic antidepressant or SSR okay that covers the maob Inhibitors let's Now cover the last drug that I want you guys to remember that increases the dopamine within the synapsis and that's amantadine all right so amantadine amantadine is an interesting drug but again man I swear you guys are going to know this pathway in and out but Ela can get taken across the blood brain barrier when it does remember we have tyrosine that actually gets converted into L Doopa and then L Doopa can be converted into dopamine and then dopamine can be taken up into these vesicles when dopamine's taken into the vesicles and then calcium is going to be brought into this neuron via an action potential it'll stimulate these dopamine vesicles to actually fuse with the cell membrane
1:20:43
release the dopamine into the synapse dopamine will bind onto the D1 D2 receptors and exert its effect on the strial neuron right now we've already talked about the comt Inhibitors the MAO inhibitor we've talked about the dopamine Agonist and we've talked about levodopa Carbidopa now the next thing that we have to talk about is amadine amantadine is really interesting so what amantadine does is again when dopamine is taken out into the synaptic Cliff one of the things that we know is it's can be taken back in Via this transporter so it can be taken back in Via this reuptake dopamine reuptake transporter I'm abbreviating it right now the problem with this you may it may seem like this is a a good thing right it may seem like a good or bad thing kind of thing this when dopamine's brought back into this actual a on Terminal two things can happen one is it can get BR back into the vesicle and be reutilized um to be put back into the synaptic C or the dopamine can get taken
1:21:35
up when it's recycled via the we just talked about it the Mao it can be broken down by the maob enzymes and that can basically render it inactive and not be able to be reutilized so the best situation is to really prevent dopamine from being reuptake in general and just keep it all in the synaptic CFT so when we give drugs like amadine what amadine is doing is it's doing two particular things amadine is going to stimulate the synthesis of dopamine it's going to stimulate the release of dopamine and amadine is also going to inhibit the re-uptake of dopamine either way if I stimulate the synthesis if I stimulate the release of dopamine I'm going to have more dopamine being pushed out into the syap aptic left if I inhibit dopamine reuptake then I don't have dopamine being brought back into the synaptic terminal to either be reutilized to be broken down so I ensure that most of that dopamine stays here in the synaptic CFT either way there's more
1:22:38
dopamine to bind on the D1 D2 receptor and exert its effect on the stal neuron now why would I give amadine now amadine is actually very interesting it actually has been found to be neuroprotective so it's been found to be neuroprotective it actually may slightly decrease the degeneration there's no proven evidence to this but it may actually decrease the neurod degeneration of particular nigral neurons so that's really really interesting when it comes down to it um so there is a question of is this neuroprotective the other thing is that it's not really a solo agent it's an adjunct so this is also an adjunct to lopa Carbidopa but here's another situation you could say yes it could be using the onoff phenomenon but I'm talking like super off phenomenon so there is a very interesting situation where somebody can have what's called an a kinetic crisis so usually this happens when someone I don't know just for some reason they either stopped taking their
1:23:44
L Doopa Carbidopa they discontinue it they've been off of it and they abruptly discontinue it and now they're off of it for a long period of time normally than they usually should be because they aren't getting getting doses of their lopa and Carbidopa they're in this period of off phase right but if it's off for a long period of time this can get to the point where the patient isn't moving at all they're not moving their face they're not moving a lot of other muscles that are helping them to breathe they're not moving muscles to push blood up into their actual heart and so because that during a kinetic crisis patients are at high risk of DVT they're at high risk of uh pulmonary aspiration increasing the risk of pneumonia right they're also at risk for hypothermia so there's really really nasty complications that you can see from an A kinetic crisis so in an a kinetic crisis what we should give to patients is Le
1:24:27
aopa Carbidopa give them back their dose that we discontinued or they didn't take for some particular reason and give them a manine and then sometimes we may also give one more drug in an a kinetic crisis if you really want to know it is a bromo uh it is a dopamine Agonist particularly one of the non- ergots we just don't often use it but there is one more drug so we can give three particular drugs in an a kinetic crisis one is we give back the elopa one uh two is we give amantadine and the last drug is a actual dopamine Agonist but it's a really powerful one um it's called apomorphine and again this is utilized in patients who have an akinetic crisis another interesting thing about aanti we it's also an anti- influenzal agent as well which is pretty cool but the general concept is that a manty may have some degree of neuroprotection but there's not enough evidence to completely support that to this point it can be used as an adjunct levodopa
1:25:21
Carbidopa particularly in patients who have an A kinetic crisis there's been a abrupt discontinuation of their levodopa Carbidopa and they're not moving at all at risk for hypothermia dvpe as well as aspiration amonia you restart the levodopa Carbidopa add on a manine and then you can also give a very powerful dopamine Agonist called apomorphine and this is usually in patients have an A kinetic crisis now because of that amadine is not really a solo agent we don't usually give this as a monotherapy it's usually an adjunct what are potential adverse effects it is an actual good drug and that doesn't have a lot of toxic adverse effects which is nice it does increased dopamine in the synapsis so you obviously have to watch out for any kind of increased dopamine within the central nervous system so you still have to watch out very mild very very mild nausea vomiting very very mild behavioral changes so you don't really
1:26:07
see a lot of these things in comparison to all the other ones but you still should watch out for that due to the high dopamine in the CNS but other things that you may see potentially within this disease is it actually can have a lot of effect on the cerebellum and so it may lead to at taxia it also can have an effect on the skin and lead to something called levido reticularis and then last but not least it can also cause some edema of the periphery so watch out for peripheral or pedal edema and that's something to think about with amantadine so again amantadine is going to increase the synthesis release and prevent re-uptake of dopamine enhance it within the synapse it can be used as a adjunct leopa Carbidopa and a kinetic crisis in combination with giving the patient back their elopa and apomorphy all right now that we talked about that let's finish off with the last category of drugs to restore the balance between a decrease in dopamine and increase in acetyl
1:27:03
choline what do we got to give we've already given all the drugs to increase dopamine let's give drugs that actually can decrease the effect of acetyl choline anticholinergics all right so anticholinergic so we have to restore that balance my friends right so there was a decrease in dopamine and there was an increase in aceto choline so really when we give these particular drugs the anticholinergics they have nothing to do with the doam pathway right so they have nothing to do with this so the problem of this disease is that there is a decrease in dopamine right there's a decrease of dopamine presence within the striatum and because of that effect that loss of dopamine on the D1 D2 receptors these patients develop a decrease in movement right we know that but the other situation here is that because there's also acetylcholine releasing neurons acetylcholine also will be released and there'll be a lot of it and acting on these colonic
1:27:51
receptors these muscarinic receptors this will lead to what this can lead to Tremors and this can lead to rigidity and so in this situation we can actually use this as a monotherapy agent in patients who have lots and lots of Tremors and lots of rigidity what are these particular agents because all these agents are going to do is you're going to use these bad boys to get in there and block the acetylcholine from being able to bind out to the muscarinic receptor therefore it will not alter the effect of what the direct pathway and indirect pathway and so because of that we will actually inhibit the trimers inhibit the effect of rigidity what are these particular agents there's two particular agents that I want you to know one is called Ben tropine one is called Ben tropine also known as centin and then the other one is called this is a heck of a name trixi fenil my gosh all right so these two particular drugs here benine biex trixin andil they work as a anti-cholinergic or
1:28:57
muscarinic antagonist you guys probably remember this we talked about this in the video on muscarinic antagonist these are going to help to restore the balance between dopamine and cocoline if I restore that balance I'll prevent the Tremors and the rigidity within this disease so if you guys remember we should this shouldn't take super long this shouldn't take super long at all what are the adverse effects of anti-cholinergic Agents so what would it do to the central nervous system so adverse effects here here we go central nervous system first one it can cause delirium right what would it do to the pupils if we go to the pupils well again what is the parasympathetic nervous system do once it cause pupil constriction so you're going to oppose that what will it cause pupil dilation so it may cause pupil dilation so the pupil will be a big what else what can it do to the glands it can decrease salivation it can decrease lacrimation so it's going to
1:29:46
cause dry eyes dry mouth so dry eyes and mouth what what does it do to the cardiac system what does it do to your actual what does the Paras sympathetic nervous system generally do to your heart it wants to slow things down so it's it actually going to oppose that so it's going to increase the heart rate and cause hypertension so it can cause tacac cardia and it cause hypertension the next thing I want you guys remember is if you guys remember we talked about the sympathetic nervous ISM generally releases norepinephrine epinephrine but there's that one situation where it acts on the what on the sweat glands where releases acetylcholine and when it acts on the acetylcholine on the sweat the acine acts on the sweat glands it actually will induce sweating so if we give a drug that actually blocks the acetylcholine on the sweat gland what would it do prevent sweating and so if I don't sweat I actually am not able to cool myself down it's because the
1:30:32
patient it develops a increase in body temperature so they can have hypothermia or pyrexia what else it can act on the git so what does it do to the git and then the urinary system generally whenever you're in a parasympathetic situation you want to allow for resting digesting right so you want to be able to poop and you want to be able to urinate so in this situation I'm going to oppose that so I'm going to inhibit pooping so I might call constipation and I'm going to inhibit urination I may cause urine retention so the other thing is it may actually cause constipation and it also may cause urine retention I know you guys remember all that from the muscarinic antagonist video but that's just a quick reminder all right so now my friends we have talked about in this video everything that you could imagine with Parkinson's drugs but we're not done let's do at least a case to understand this stuff all right my friends let's do some case
1:31:19
questions here so first one you get a 75-year old man with moderate Parkinson's disease no longer responding to anticholinergic treatment primarily for trimmers not so much the brainia again brainia is not as well treated by the anticholinergics it's more the drugs that increase dopamine uh in those situations if we decrease the acetylcholine effect we get more of the reduction in trimmers and the rigidity Factor not so much the Brady kyasia so at this point we need to come up with a good treatment plan for the patient that will help with the Brady kyasia and the first one always first line is levadopa generally patients greater than 65 years of age we always start off with but though but if they were less than 65 and it was more of a milder case we could consider like the dopamine Agonist like renol or premy packs all things of that nature but since this patient's already 75 years of age and they've already been treated for the anticholinergic for the
1:32:08
trimmers and they already have Brady kyasia and they're more of the moderate state I'm going to go for the first line which is levadopa so if we look here I can already tell you that the answer has to be B oh and I just clicked it um but we know that it's got to be this one CU there's no other option here that we see for levadopa it has to be levadopa and you always have to give levadopa with Carbidopa because when you give Carbidopa it reduces the ability of levadopa getting converted into dop uh the dopamine because Carbidopa is a dopa decarbox inhibitor so you have to give levadopa with Carbidopa and it was literally the only option now the other reason we can give that other drug there is in Capone in Capone is again a comt inhibitor particularly a peripheral comt inhibitor so when you give these two drugs think about it you give levadopa levadopa you want to cross the bloodb brain barrier Carbidopa will actually inhibit the dopa
1:33:02
DEC carboxilate so that the levodopa doesn't turn into dopamine okay second thing is that the levodopa can also get broken down by comt Inhibitors in the periphery into 3D an inactive metabolite that can't cross the bloodb brain barrier and if I give a CT inhibitor I'll inhibit that process and make sure that levodopa is essentially crossing the bloodb brain barrier so this is a great combo here to ensure that actually all of the levadopa gets acrossed none of it gets converted into dopamine none of it gets converted into 3D and this is actually a great pill that actually comes in a a combination pill I think they actually call it um sto so it's one of those drugs that actually can come in a combination form which is nice and easier for compliance all right so that's that one second question peripheral adverse effects of levodopa include nausea hypotension and cardiac arrhythmias and this can be diminished by including which drug in the therapy
1:33:53
well remember when we're talking about levadopa causing nausea or vomiting via the stimulation of the chemo trigger Zone hypotension via acting on the dopamine receptors on the blood vessels kind of dilating them and leading to orthostasis and cardiac arhythmia by acting on the beta receptors on the heart to increase heart rate we're really talking about dopamine and if I gave levadopa and I didn't give any carb Carbidopa guess what most of the levodopa gets converted to dopamine so therefore it causes nausea vomiting hypotension cardiac rmas which drug would inhibit the conversion of levodopa into Carbidopa I'm sorry into dopamine it would be Carbidopa I kind of gave you the answer but again it's got to be Carbidopa here because Carbidopa reduces the ability of levadopa to get converted to dopamine and it's that excess dopamine in the periphery that causes these cardiovascular effects and nausea okay it wouldn't be amantadine it wouldn't be renol it wouldn't be antic
1:34:46
compone okay all of these would actually potentially even cause these effects as well because they increase dopamine all right let's talk about the next one here which anti-parkinsonian drug may cause vasospasm I briefly went over this in the video remember I told you that there's two types of dopamine Agonist there's the ergots and the non- ergots and the ergots we don't utilize as much anymore such as bromocryptine um and pergolide and the reason why is because they can cause pulmonary and cardiac fibrosis but the other thing I kind of briefly mentioned is that can actually cause vasos spasma and this can actually cause patients to like lose some of their fingers or toes because it can really really constrict down of their vessels and it can cause arthro malasia it can cause actually like iosis and necrosis of the digits as well so we don't really utilize bromocryptine and pergolide for that reason anymore and that's why we prefer the per paol and
1:35:32
the rinol which are the non- ergots because they don't have any of that vasospastic effect they don't have and it's also important because they can actually cause vasospasm with the coronary vessels as well that'd be problematic if you have coronary vasos spasm what could that increase the risk of it can increase the risk of like a myocardial infarction or some type of anguna as well so watch out for bromocryptine especially if a patient has underlying coronary artery disease probably want to avoid that drug all right so that would be definitely here in this situation bromocryptine and if pergolide was there it would be pergolide as well so that would be that uh option there so again that covers all of these questions that we need to kind of quickly overview what we talked about here on the Parkinson's medications of the Parkinson's pharmacology I hope it made sense and I hope that you guys enjoyed it as always until next time
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