hey this is Dr Bustdy and we're in our section of neurology where we're going to be doing an overview of the diagnosis pathophysiology management of Parkinson's disease Uh so I'd like to start off with a little bit of background information and then we'll lead into the you know specific information as relate to Parkinson's uh diagn pathophys and then the diagnostic criteria There are a number of neurotransmitter systems and neurotransmitters um in the central nervous system and they exert uh a number of different effects and pathways uh and I try to list what some of those are here as just a overview as we think about the context of the central nervous system in relationship to other disease processes because and interestingly even in Parkinson's disease we have overlap with even psychiatric um problems and so and that ends up becoming a big issue as part of the overall management with these patients and in addition they also develop at a higher or greater risk for developing dementia And so when you think about things like Alzheimer's disease or other forms of dementia and then the drugs that we use to try to manage those patients or patients with psychiatric illnesses and the drugs that we try to use there's a lot of crossover and sometimes one drug class can worsen or exacerbate uh disease of another um situation And so we have to kind of think about all these And so the two neurotransmitter systems that we're going to be considering uh in particular today uh is dopamine predominantly and most of our drug therapy is targeted at trying to increase either the release the production decrease the metabolism or inhibit the re-uptake of it so that we maximize the amount of dopamine present in the central nervous system At the same time acetylcholine in the cononergic system also plays an important role in the overall balance of muscularkeeletal coordination and movement in this disorder Um and so those are the two main things There is some activity of glutamate which we'll see here in a minute within the um uh central nervous system in Parkinson's and it is our major excitatory neurotransmitter Uh we'll also see that GABA plays a role in part of the interconnections and neurons that are talking to different uh parts of the brain U and it's our major inhibitory neurotransmitter And these drug and these neurotransmitters when they're released um in their proper context and areas create balance Okay Everything's in pro and con everything's in a balance of this way or that way And too much of any one thing creates an imbalance obviously And that's one of the things that happens in Parkinson's disease where we have an imbalance of not enough dopamine too much coneric activity that affects both our glutamate and GABA release within inter neurons and the complex nature of it And I'll show you a diagram here to bring it all together But I wanted to lay a little bit of the core groundwork for some of these Now we see GABA and glutamate show up in in um conditions including epilepsy and seizures obviously norepinephrine serotonin and depression um anxiety disorders and those types of things And so um again trying to integrate and understand because you can't learn things only in isolation So Parkinson's is a you know been around for a long time uh James Parkinson is the one who originally described it and it was an described as an involuntary tremulous motion because one of the core defining features is that they have a resting tremor that improves with voluntary movement Um obviously this disease is growing in its nature as we keep people alive longer and if you look at the overall incidence of it it sort of uh once you get over age 65 the incidence starts to rise fairly rapidly Unfortunately also what ends up happening is they have a rate of decline in their survivability and so there's a greater mortality associated in patients with this disease and some of our drugs have been known to improve the survival uh of patients when it started early on things like levodopa carbodopa in particular So what is causing it Well as I mentioned just a minute ago there's a problem where there's an imbalance between dopamineergic neurons So dopamine producing neurons specifically in the substantia uh and specifically also an imbalance of too much coneric effect And so why does that imbalance happen Well there's no one specific cause um there are environmental um exposures and toxins that have been attributed to it because they when they're present especially in animal models they mimic some of the same features of Parkinson's disease Um and so there may be also damage to the neurons from free radicals or inflammation And this is where efforts have been going on to try to figure out ways to reduce the inflammation that may damage some of these neurons Um and then certainly drugs can cause or induce Parkinson's like features or pseudoparkinsonism Um antiscychotics because of their antagonism to the dopamine receptors have classically been able to do that Mtop meopomide or known as reglan which is one of our promotility anti-imetic agents uh that we use for GI related issues um in addition to other things but is also has dopamine antagonism um type of effects and then there have been cases of effects of within calcium channel blocker specifically the non-digital period and calcium channel blockers and valproic acid so as I mentioned dopamine is insufficient uh and one of the things uh that I want to try to drive home is that when we try to target the treatment of this condition we're hitting it both in the periphery and the central nervous system So this diagram while very busy we're going to see it over and over again Let me just orient you to it just a little bit So this dotted line that you see here is reflective of the bloodb brain barrier if you will Oh you got to put on an imaginoscope But this box that's around here and the is trying to can reflect the central nervous system versus everything out here um is the periphery or the peripheral um you know blood flow and organs and all that other stuff Okay Now if you look at L-dopa which is one of our treatments of choice uh L-dopa uh or well dopamine does not go through the bloodb brain barrier very effectively and so that is why leodopa or l-dopa was formed so that it can penetrate the bloodb brain barrier more efficiently u by reducing its hydrophobicity as compared to dopamine but uh one of the things that's important to recognize is that L-dopa does get metabolized in the periphery um by a number of enzymes elamino acid decarboxilase okay And that forms dopamine but it also forms dopamine in the brain once L-dopa gets in there because elamino acid decaroxilase or what is known as also called dopaaroxilase um again converts L-dopa to dopamine But there's also um enzymes called catakolomethyl transferase or compt uh that also produces end products uh we have also monomine a uh oxidase um enzymes that are also known to create metabolites and it's these some of these endroducts of metabolism that is actually thought to also contribute to the pathophysiology So when you metabolize dopamine some of the end metabolites seem to be pro-inflammatory may cause damage to neurons at least in animal models Um and so there's been a theory that for a number of years that if we block or decrease the amount of dopamine metabolism then we theoretically will reduce the overall progression of the disease because we're protecting those dopamineergic neurons from the damage of some of these antioxidants and pro-inflammatory uh metabolites While that's been interesting pharmacologically and interesting in models um it has there's no real solid evidence that proves that to be definitive for most patients Um however if you think about drugs that reduce the amount of dopamine um being present it theoretically offers an advantage and those would be the dopamine agonist catakolmethyl transferase inhibitors monomine oxidase inhibitors in particular especially those that are selective for B And so what has historically been thought is that leodopa um and carbodopa uh may actually contribute to the progression even though it increases survival length compared to normal controls that um that don't get treated Um the uh the other drugs dopamine uh receptor agonist and the uh catakol methyl transferase monominoase inhibitors they are preventing the metabolism or they directly stimulate the receptor and so we don't generate those metabolites again I'll come back to this a little bit but I'm just kind of laying the groundwork as we think about the pathophysiology being probably multiffactorial probably a genetic predisposition that is factored into this there's environmental exposures and toxins that sometimes can get into the central nervous system that may damage these nerves But the goal is to try to reduce any inflammation that may occur Once patients develop Parkinson's disease they're also at higher risk as I mentioned of getting dementia which then creates more problems because we don't really have good treatments that treat the underlying pathophysiology of beta amalloid pack plaque deposition neuritic plaques uh hyperphosphorilated towel proteins that cause neuropibrillary tingles We don't have drugs that really stop those things We only have drugs that improve the coneric activity which is only really one of the manifestations of that underlying disease process in Alzheimer's disease or antagonizing the NMDA receptor from glutamate activity um using drugs like nmena that we see in in in Alzheimer's disease So again there's this constant balance and sometimes the drugs that we might use for Alzheimer's disease could worsen Parkinson's features and I'll come back to that briefly in the lecture So the normal physiology is dopamine Now I'm not saying is exactly equal to but there's a nice uh balance It's kind of like a tug-of-war where both sides are sort of winning right There's a little bit of pull and give and take but there's an overall net balance And in Parkinson's disease we have um decreased amounts of dopamine producing neurons And so therefore we have too much coneric activity coming through and being modulated part of the central nervous system And this results and this is a sort of a summary of what ends up happening is but we ultimately result in excessive inhibition to the theamic and brain stem nuclei and that excessive inhibition of the overall influence on those two areas creates a problem with motor movement and coordination So where they lead to a aisia muscle rigidity and then they have what is called a resting tremor not a intentional tremor Intentional tremor is when you go to try to pick up a glass you're reaching out to go get it and you're shaking That's intention You're intentionally trying to move your hand Whereas in Parkinson's it is a resting tremor Their hand is sitting there on their lap and it's shake and it's having a tremor But when you ask them to pick up something that the tremor then goes away Um and so in when you look at the underlying problems the dopamine producing neurons appear to be depleted and there are so as a result of that there is no overall inhibition of the cononergic neurons Then what happens is is that there's too much coneric stimulation and that contributes predominantly to our tremor the dopamineergic parts seem to contribute to the motor fluctuations and disability contributions as it relates to the disease Now there are a number of different subtypes of dopamine receptors and when you activate or antagonize those receptors they do exert different things Uh so for example the D1 receptor when they're stimulated is associated with side effects of diskynesia stimulation of the dopamine 2 receptor uh is where most of some of these clinical improvements occur But unfortunately it is also associated with many of the adverse reactions including hallucinations So if you stop and think about excuse me uh schizophrenia for example um and what are the drugs that we use to treat schizophrenia We use antiscychotics that many of times antagonize dopamine but also modulate the activity of serotonin But if you antagonize dopamine and we improve the hallucinations therefore the underlying assumption is if I give somebody dopamine or I increase their dopamine in their central nervous system then I could cause schizophrenia like features No different than antiscychotics can cause Parkinson's like features because they antagonize the dopamine receptors and it comes from the interactions with these different receptors and different drugs bind different defi affinities or potencies to these receptor subtypes and that creates some of the variation that we sometimes see in the response Now as we try to pull this all together okay Because I'm getting ready to dive a little deep that may cause a seizure in some of you Uh but um but what I'm not trying to do is make it complicated I'm trying to put it together the big picture This is sort of a big picture summary And if you understand this fundamental concept or this slide you're going to be fine The next slide is a lot more detailed of this representation um but it's more accurate based on the models that we understand So we like I said the substantia the dopamineeric producing neurons are lost So we basically lose these over time They get damaged They degenerate They go away Their extensions of their nerve axons to the other parts of the brain are lost And as a result not only are they not making the the dopamine but they're also not secretting those and having nerve intervations to other parts of the central nervous system and specifically the strriatam where the cononergic neurons are coming in and influence other pathways And so you lack too little or you don't get enough dopamine in these situations And what ends up happening is you have an excessive coneric output Again you've created an imbalance This causes a net inhibition okay on the cortex which is where your motor function is really regulated And so that impairs the initiation of movement as well as coordination of that movement And so if you think about the imbalance there's too little dopamine and too much acetylcholine or chonergic effects And so that's why it weighs itself down over here on the scale And our goal is to try to maximize the dopamineergic contribution so that we reduce the acetylcholine contribution and we then create a more balanced system That's all we're trying to do Now we can do this a number of ways We can give somebody dopamine or L-dopa We can prevent dopamine or L-dopa from being metabolized and then allowing it to be metabolized in the brain to dopamine We can prevent dopamine from being metabolized by blocking catakolomethyl transferase or COOMT or by blocking monomine oxidase specifically type B right Or we can act on the receptor ourselves by giving them a dopamine agonist So you can see that we're affecting a number of different mechanisms that can modulate the activity of the dopamineergic nervous system within Parkinson's disease to create again this balance Visually that's all we're trying to do Uh I realize that this next slide here is very complicated and makes lowers your seizure threshold and can put you into status epilepticus but uh hopefully you know how to treat that by giving yourself some IM madazzylam or ver or adavan right all right just kidding right got to have a little bit of fun here keep it fun uh so this is obviously a more complicated diagram of what I just showed you but here's your substantra okay uh this is the cerebral cortex that I was mentioning and as I mentioned there's a net inhibition on this area up here Okay So what happens Well you can see here that we have a number of different uh communication points between parts of the central nervous system in the brain Right And so as I mentioned the substantigra produces dopamine and it influences that stratum which is where the cononeric neurons are normally placed Okay Now you'll see here that GABA as I mentioned early on in the lecture is our major inhibitory And that's why you see this little negative sign that's here So when they're released GABA is now working it inhibits these components which is the substantia uh reticularis and then the globus paladus interna here This is the globus paladus externa over here Now the um when you you see that there's an inhibition so it's then going to suppress those but then you also have neurons over here that are activating again constant tugof-war and I know it seems confusing but you've got negative or inhibition input over here you've got excitatory input over here and these then get influenced by how much they're released so how much GABA is being released and so remember GABA being a major inhibitory neurotransmitter If the net effect is too much of this over here then we're going to inhibit the thealam the theamic area right the phalamus that would then decrease the amount of glutamate And so that creates the net the net inhibition because you see how the arrow turns into a dash because it's showing you that there's a net inhibition on the thealam um the phalamus that then reduces the amount of glutamate that's released which then inhibits the cerebral cortex So that's why I was saying the net effect Now there are what we call the direct pathway and indirect pathway And I put the the pathway there for you Um so you could sort of see what's happening between these two systems But there's a tugof-war going on here And remember you have too much excitatory input okay activation of these two components of the central nervous system here Okay And what that does is it causes too much GABA to be released That is too much inhibition on the th theam uh thalalamus sorry thealamic area Uh and that then inhibits the glutamate release and that creates a net inhibition which means then the output from the cerebral cortex back onto this these other components in the central nervous system and the spinal cord area then lose its regulation So you can see that the circuit is affected and hopefully it makes a little bit of sense What I'm going to try to do is show you as we go through the drug therapy where the drugs are working on here and the effect that ends up happening But all of you can really think about or if you just imagine that if we can turn this around by increasing the dopamineergic stimulation here in the strriatam then we will slow down all these thick arrows and we will start to bolden this again and therefore it creates less net inhibition and then it allows this circuit to then communicate again factoring in initiation of motor movement the fluidity of your motor movement fluidity being how smooth and coordinated it is um is influenced by this circuit Okay so I hope I know it's complicated Hopefully you're not in a postal state from your seizure but uh it's complicated but I hope that it made sense Okay uh recognizing that that this is still being worked out We don't know every detail of it Some things are still being looked at in animal models and those kind of things but this is the main stay of the thought process and is probably more relevant for your board exams But you'll also see that this is true in in clinical practice So our goal when we're doing the diagnosis we want to make sure that we don't have something else causing the problem So rule out medications I talked about antiscychotics medicopramide valproate calcium channel blockers that have been associated with causing some of these types of symptoms Some of the pre-clinical testing that has been talked about and done or is what we call positive emission tomography or spec uh tomography basically which is where we look at markers of metabolism blood flow and and circuits in the brain and looking at those areas within that model I just showed you on the previous slide and seeing how they light up compared to the normal patient without Parkinson's disease But nine times out of 10 the diagnosis is based off of a clinical uh exam and history And so these patients have at least two of the following So they have muscle rigidity resting tremor that improves with voluntary motion and then postural instability Now when we talk about resting tremor again this is a rest It's unilateral usually and it improves with voluntary movement which is different from a uh uh a voluntary tremor right or intention tremor when you're intentionally trying to pick up something Now the the rigidity of the muscle here is a real again incoordinated uncoordinated and sort of really abnormal contraction or disc type of kinesis and so people have described it as this cog wheel rigidity of their arm So if you hold their arm and you make them kind of go back and forth I can do this very quickly But if if I if I'm as I'm pulling it up it starts to vibrate right And you get this sort of intermittent muscle contraction You get this sort of cog wheel sort of effect And it sort of has a stop and go on passive motion because they don't have good muscle relaxation and coordination that's being uh balanced in that system Their motor movement is also slow Okay So if you've ever seen them they you know they kind of shuffle around They move like a robot real slow And those slow muscle movements also create problems because if they lose their balance they can't catch themselves very efficiently and they can't protect themselves very quickly And this is where when they fall they have injuries breaking their hip hit their head And if you think about many of these patients they're at higher risk for osteoporosis Many of these patients being older may not be on other co other have other coorbidities including where they need to be on anti-coagulants or antiplatlet drugs and now they fall because of their lack of coordination their postural instability their slow motor movement and they hit their head on the way down and that's what ends up killing them or they break a hip and then they end up having significant functional decline as a result of that as a result of that Right Um there are others um manifestations microraphia you know this is instead of having nice you know fluid movement of the you know writing they write real tiny and it's squiggly right so they have this sort of like real tight micro um graphia is what they call it uh drooling again because of the imbalance of the central nervous system increased sebum production microphonia remember so they're not moving their mouth They're tucking like this right very moving their lips because they don't have good fluid motor movement Uh they can have dysphasia and again uh if you think about the mechanism of swallowing so dysphasia is difficulty swallowing Odinaphasia is pain with swallowing but dysphasia the first onethird of your esophagus and the posterior oral ferinx is under skeletal muscle control For the most part you can tell yourself to swallow Once you get past the first one-third the rest of the twothirds of your esophagus is pretty much under control of the autonomic nervous system You have no control Once you started to f swallow a food bolus it's going to move all the way down through the esophagus without your knowledge and control of it So patients with Parkinson's disease can actually have problems with aspiration difficulty swallowing And this is one of the benefits of having dosage formulations available in trans dermal routes or liquids where they can swallow things maybe a little easier than a tablet Uh and so they'll see you'll see that we have some of those examples um in some of our treatments Um and then certainly constipation because constipation is a a a muscle related thing although it's smooth muscle typically under the control of the autonomic nervous system All right So what are our treatments Well these are all the different pharmacologic options We're going to kind of go through each class one by one and I'll try to highlight the important points about them and little clinical pearls and then tie it back into the pathophysiology so that it hopefully makes sense to you Okay So again our goal is to move L-dopa and remember we want this pathway because we want to get dopamine in the brain Now once it gets in the brain we really don't want it being metabolized If we could stop that that would be nice Okay And so we have drugs that target these enzymes to stop the metabolism But those drugs also work in the periphery and we'll see those in a minute Okay We also have drugs that prevent the peripheral conversion of L-dopa to its metabolites Okay And so that's leodopa carbodopa carbodopa attacks this enzyme in the periphery but not in the central nervous system Okay Um and so you see here our goal is to increase dopamine whether it no matter what med we used and we're trying to al sometimes occasionally use anticolinergic drugs to slow down the input Obviously using anticolinergic drugs in an older patient is not advisable in most situations Nothing in these things work right you'll see that they have a lot of side effects and complications No different than the colon eststerase inhibitors for the treatment of Alzheimer's disease have a lot of side effects and sometimes the net effect is more negative than it is positive U but again our goal is to go from there to there and so if we can increase dopamine that is the goal So carbodopa leodopa is known as cinnament historically there is a controlled release uh formulation or extended release formulation that is available So most people start out with immediate release to try to figure out what dose they need and then they can kind of consider converting over to long acting if they don't want to try to have to take multiple pills throughout the day Now let's break down the two components We have the L-dopa or leodopa and then we have carbodopa Well in the past before carbodopa came out levodopa was given and you had to give it at very high doses because not very much of it would make it into the central nervous system because it would get metabolized in the periphery and as a result of getting metabolized in the periphery instead of going into the central nervous system it caused a lot of side effects and so that's where carbodopa came along and inhibited the peripheral metabolism Okay By inhibiting elamino acid decarboxilase or also known as dopaaroxilase You'll see those terms used interchangeably in the literature Um but by blocking that now what we we do not need as much drug and so we give lower amounts of L-dopa when it's combined with carbodopa that also facilitates greater penetration in the central nervous system where it needs to work and reduces the overall side effects And so historically it is considered the gold standard for treatment and Parkinson's disease Um and it has been known to prolong survival Um and so it does have an effect on mortality especially when compared to patients who are not treated with them Uh but it has also been thought to unfortunately contribute to the progression of the disease because again you're giving a precursor to dopamine Dopamine goes on to get metabolized and as I mentioned in the pathophysiology section some of these metabolites may be damaging the dopamineergic neurons themselves and so you know theoretically we're worsening it but we do know that it improves the survival in these patients as well as their improves improvement in morbidity uh when we start these drugs early Now again it's a double-edged sword okay Nothing is perfect here Um but it tends to work more on the brada and patients with disabilities from motor dysfunction as well as rigidity It doesn't work as well on tremors Remember tremors are predominantly controlled by the colonergic system Now think if you stop for a minute if we increase dopamine we will have an effect on the colonergic system So that's why we don't start off with anticolinergic drugs first Not only do they have enough side another bunch of side effects like blurry vision constipation dry mouth all these other things Uh if we start out with the dopamine and fix that problem a little bit then theoretically we will slow down the response and improve even the resting tremor as well So this is applying it back to our diagram Here's our leodopa or L-dopa So that we don't want it to get metabolized in the periphery So we block that Now you see this arrow here where it's sort of bouncing off the bloodb brain barrier there Remember my my little dotted line here is the bloodb brain barrier So things don't go in if it shouldn't go in and goes in when they should Now L-dopa goes through a transporter that is uh similar uh to some amino acids and it is has amino acid-like structure and as a result uh amino acids can or proteins can uh which amino acids make up proteins uh can compete with its movement and we'll talk about that in a minute as it relates to diet and also then we'll talk a little bit about vitamin B6 because l amino acid decarboxilates requires vitamin B B6 six to work and highdose vitamin B complex vitamins and particularly B6 which is known as paradoxine can actually increase the metabolism of of levodopa in the periphery and in the central nervous system and may lose some of the beneficial effects of the drug Um so carbodopa bounces off It does not penetrate the bloodb brain barrier And that's an important mechanism to understand because if it did get inside of the and central nervous system then when L-dopa got inside of the brain up here then L amino acid decarboxilates wouldn't be able to convert it to the dopamine so it can work So we don't want carbodopa getting into the brain We only want L-dopa to get in the brain so that the L amino acid decarboxilates in the brain can do its job and generate the dopamine Right This is what we're trying to do We're trying to facilitate this movement in All right Now as I mentioned we start off usually at a um low dose and we titrate through multiple doses throughout the day with an immediate release And that's because you need to figure out what dose is going to work for them This is where a diary of your symptoms really comes in for patients to to do And what I mean by that is they almost do an outline throughout the day and they say this is where my muscle movements are good not well my tremors are bad And they you try to map it out almost like throughout a day in a graphic formulation to figure out well I took my drug here and this is when my symptoms was were improved during this time frame but this is when my symptoms also stopped being improved and they started being exacerbated again and I need another dose Once you kind of figure that out then you can determine the frequency of administration There is no one sort of size that fits all for all patients And that's important to recognize as you use these drugs you're going to be manipulating things on a personalized basis Not everybody's going to respond the same and you're going to have to manipulate one drug drug class add on another one when one drug class isn't working all this kind of stuff But it's going to be specific to the patient and their symptoms And doing a diary by either the caregivers the family and the patient incorporating being involved in that if they're not having dementia uh is important as to the overall proper management Now once you sort of figure out what it is then you can consider a controlled or sustained release option You just need to recognize that the overall bioavailability is less with the extended release options So you have to sometimes you have to dose up the drug So it's not a onetoone conversion You have to increase the dose by about 20% when you convert them to maintain sort of the same effect Now obviously the immediate release sort of give these peaks and troughs peaks and troughs and obviously during the peaks you know your symptoms could be controlled or maybe too controlled and cause motor movement problems okay giving too much drug and then in your trough periods is when your Parkinson's like features are even worsened right and so the the point of a sustained release is to try to create a little bit of a balance so you don't have that labile sort of effect the downside to it is that it's const constant dopamine exposure to the brain and we're going to see that that's a problem as it relates to side effects because as I said at the beginning in the pathophysiology giving somebody dopamine or having too much dopamineergic stimulation can do a number of things One it can cause hallucinations and psychotic features but it also can start to reward the uh to stimulate the reward pathway that makes us lose our inhibition and do things that are very self-gratifying and about me me Uh and we'll see that in a in a with a dopamine agonist in particular Uh patients get into pathologic gambling hypersexuality all kinds of things They've lost their entire re uh retirement accounts lifestyles I mean everything Their lives have been destroyed sometimes by these drugs and it's thought to because of the dopamineergic stimulation of that reward pathway So the dosing is going to be different for each patient Just realize that that's why we have number of different dosage formulations there and the frequency is different Now it says here best if taken on an empty stomach and and or a consistent diet because a high protein meal appears to compete with the movement of uh L-dopa into the central nervous system which may influence its overall efficacy and so keeping diet consistent if you can take it on empty stomach a stomach that is ideal Now it says here avoid uh use of intermittent especially highdose vitamin B6 Now B6 is known as pyodoxine and sometimes we use highdosese vitamin B6 in certain patient populations Say for example if they're on I inh for tuberculosis type of treatment you know you might need that Okay now uh what's going on Well remember vitamin B6 is a co-actor for L amino acid decarboxilates not only in the brain but also in the periphery and so if you give high doses of B6 you can actually start to shunt and override some of the inhibition even by carbodopa I will say though the evidence that supports that is weak and most of the time carbodopa blocks so much of the elamino acid decarboxilates that even highdose paradoxing uh doses uh generally are not going to significantly decrease the efficacy or cause more side effects because L-dopa is being converted to dopamine in the periphery But it is just something to recognize board exams and and things like that like to ask that kind of question because it gets down and dirty into mechanisms and underlying pathophysiology of the overall situation Now side effects and you're going to see this is true for any drug that increases dopamineergic activity Again whether it's causing it to be released in the central nervous system you're decreasing the metabolism you're preventing the re-uptake you're stimulating the receptor they all cause similar side effects And so that makes it easy in trying to remember them You see them they vary obviously in their degree and amount of influence based on the formulation and the dose but that's they all do sort of the same thing They have a lot of GI side effects And part of this has to do with its irritation to the gastric uh tissue but also uh binding to the chemoceptor trigger zone which remember is a part of our central nervous system that doesn't have a significant amount of bloodb brain barrier to it So that if we get exposed to chemicals that we shouldn't be having the body wants to try to get rid of it And so if you start to vomit by direct stimulation of chemoceptor trigger zone then you're going to be expelling out what you shouldn't have ingested Um and so that can happen nausea vomiting uh tacocardia hypotension Um if you think about some of the neurotransmitters that dopamine gets metabolized to it would make sense why you get tacoc cardia you would think that they could get hypertension and that may actually happen if they take a monomine oxidase inhibitor with the drug But many times these patients will experience hypotension which may sound a little counterintuitive at first but the relevance is that clinically this can happen and remember they already have brada postural instability they if they start getting dizzy and lightheaded from hypotension and they fall again they can hit her head you know cause an internal bleed they could break a bone and now cause functional decline um and as I mentioned with dopamineergic um stimulation you not only can stimulate the reward pathway but you can cause psychotic features and that's where these delusions come up delirium they can start having really vivid dreams and nightmares and then the hallucinations are going to be worse with the sustain stain or time release formulations because instead of having this peaks and troughs where you have lower levels you're having a constant exposure of dopamine to the brain Just you know keep hitting it because you have a continuous release formulation being provided Now what about the dopamine Okay So the other thing that I wanted to mention before we leave carbodopa leodopa is that while many patients get started on this first especially maybe earlier in life you know right so remember there's thoughts that starting earlier may actually improve survival and so we don't want to delay that like I said there's also concerns that it might be causing the progression of the disease because of the metabolites and the oxidative damage that may occur to the dopamineergic neurons Again that's not significantly proven in good data uh that proves causality but it's certainly a concern that we want to keep in the back of our minds But uh you tend to lose the effect over uh 5 years It starts you start losing the effect By 15 years many patients will have lost most of the effect of the carbodopa leodopa And so what you end up seeing during that time is you have to increase the dose or the frequency of administration or then what ends up happening is you add on some of these other drugs like dopamine agonist that we're going to talk about catakolmethyl transferase inhibitors monomine oxidase inhibitor to again try to boost up the amount of dopamine but when you do that the side effects start to go up right because you're you're giving multiple drugs and you're needing to drive it And why does this why does that happen Well again the disease continues to progress And that is an important counseling point not only of the patient but it's an important counseling point to the caregivers and the family who need to recognize that while these drugs can sometimes reduce the progression and increase survivability I'm sorry not reduce incre improve the survivability and morbidity uh related to their um life It does not reduce the progression It doesn't stop stop it doesn't halt it Um they will still end up going on to needing more having more advanced disease and that's part of the problem That's where these drugs like dopamine agonist are used Now dopamine agonist tend to be used uh sometimes in patients who are a little bit younger uh who have early stages of Parkinson's disease uh because they can tolerate the side effects But uh we always see these drugs sometimes being added on when we sort of felt like we've maximized our leodopa carbodopa therapy are not getting adequate control recognizing there's a balance in the simp side side effects Now there are some drugs that are no longer being used I only listed them here for historical context because we it's important to learn from past drugs and put things in their proper context These drugs are associated with valvular fibrosis within within the heart Um and so they were pulled off their market because of their structures being erotamine like And so now we only have really a couple agents left They kind of all kind of come and go based on their profile There are some safety concerns with these drugs and I'll point that out Um so let's go through these agents So as I mentioned we might use these sometimes early on in a very young patient but the reality and and because they're not generating metabolites they're only stimulating the receptor We theoretically are going to reduce the progression of the disease Maybe a little bit neuroprotective maybe Uh again these are discussions and you'll read about them in papers and reviews and books We'll talk about them But again the there's no good definitive data that truly supports that as being true for in human uh clinical trials Although there's sort of subgroup sort of an analysis animal studies that have suggested this to be true And in theory pharmacologic theory it makes sense And so it is worth considering Um as I said we usually add it on when uh we start losing the effect but you're going to see greater side effects especially in our older patients Now remember that D2 receptor u is the one that provides a lot of the therapeutic benefits but it also comes with a lot of that side effect stuff that we didn't want right All right So our dopamine agonist literally function like the nerve endings in the stryatum So they're directly stimulating the dopamine receptors in the stratum which then you know shuts down some of these abnormal pathways that then facilitates movement of the circuit again So um so again we have different types of dopamine receptors D1 D2 and just recognize that they vary a little bit I'll point some of those out here in a minute uh you will see here that the symptoms also again because the disease progresses pro progresses on you only get about a couple years and this is not something that you want to just abruptly stop you want to taper these drugs now and just like I said before any drug that increases uh dopamine causes a lot of the same side effects so you get a lot of the GI side effects for the same reason you stimulate the chemo receptor trigger zone you just get these side effects hypotension uh again hallucination psychosis nightmares sometimes even worse patients is throwing multiple agents As I mentioned the urgot structured similar structured uh agents that were on the market in the past caused fibrosis of the cardiac valves and so they were pulled off the market because of their uh safety concerns Now you see also listed here dangerous uh risk for sleep attacks Think of uh uh patients who have narcolepsy you know they just immediately go into REM sleep And so this is almost exactly like kind of what happens They just immediately you know doze off Like some of you right now listening to this lecture right Uh those of you are awake got that Uh but uh you just have these sleep attacks you know you just your head just bobs you know you can't handle the pain and suffering anymore Uh no I get it But no this is real right And so obviously if they fall they hit their head they break a leg break an arm right Break a hip if they're driving which you know plus or minus shouldn't be doing anyway right Then that can be concerning In addition to the stimulation of the dopamineergic pathway you're going to stimulate the reward pathway And so one of the other things that's not listed on this slide but is listed on the slides that I'm getting ready to cover is the concerns for uh pathologic gambling hypersexuality doing things that basically most people would have some inhibition against Um and uh people have lost like I said their their retirements their homes their families I mean it's and there's now obviously a lot of lawsuits and stuff like that Now we also use dopamine agonist for restless leg syndrome But the doses that we use in in restless leg syndrome are significantly lower than what we would use in Parkinson's disease and is only dosed at bedtime uh right before bedtime because that's usually when there's symptoms they cough restless okay because their legs or they have tremors and so we take a low dose of this at bedtime and it can um treat that Now loresus leg syndrome is caused by some other things including iron deficiency anemia and so you should treat that first before you move on to drugs like this So let's just kind of walk through a few of these agents We have pramipexol or muripex immediate release and extended release formulation You see again Parkinson's and restless legs as indication That's true for these agents I put the doses here disease restless leg Again just trying to show you the differences in the frequency So with Parkinson's disease three times a day because you need control throughout the day whereas restless leg is a low dose at bedtime Okay Uh you see that they modulate the receptors D2 and D3 um as an agonist Again D2 is where you know I was talking about early at the beginning in the pathophysiology but the side effects are all the same that I just mentioned here A few other things to keep in mind A little bit of peripheral edema Okay Uh can sometimes happen All right Um also there's been used in patients with depression and fibromyalgia There's uh some special populations I don't know that you'll be asked that test on a test question but just to try to be a little bit sort of complete Now the extended release option offers a once a day version instead of having to take it three times a day And that's its benefit Uh Rapinerol again immediate release and then we have an extended release product Again approved for both Again I try to give you the doses here okay for you uh again works on D2 D3 So we're really trying to avoid the D1 It is a 1A2 major substrate So there is a risk for drug drug interactions by inhibitors of 1A2 and classically those are known as amiotarone simetadine cypro being the main uh drugs historically So if you were to ask a drug drug interaction that would raise the concentrations which would then worsen a lot of these side effects uh this would be uh those three drugs in particular which are used still in somewhat in clinical practice would be the more likely to do that Um roticotine which is new is a transdermal patch uh again approved for both restless leg and um Parkinson's disease Now the transermal patch is nice because it again avoids the gastric irritation that can cause nausea and vomiting It also uh decreases the first pass metabolism and the amount of drugs that needs to be given that would then stimulate the chemoceptor trigger zone Uh and so by if someone has also trouble swallowing this is helpful So there's a lot of little benefits to using the patch uh including you know difficulty swallowing if someone has you know Parkinson's features where they have dysphasia as part of their symptoms All right What about a catakolmethyl transferase inhibitors comp inhibitors We have intapone tolcapone We only really use one of them We'll talk about why But remember these are working on the periphery and the central nervous system Well one of them works in the central nervous system They both work in the periphery and they block the metabolism So the side effects make sense They're all the same ones as you know what we we saw just a minute ago But unfortunately there have been case reports not many but a few case reports of tocopone induced acute liver failure Um and I believe they those patients died if I'm not mistaken Um and so andapone and tocopone both work in the periphery but toapone works in the central nervous system which you think was as a benefit right remember we yeah we want to block it in the periphery but we want to also block it in the central nervous system not only to pre so that dopamine can stick around a little longer but can also prevent the metabolites and so theoretically has a neuroprotective benefit kind of like the dopamine agonist that I'd mentioned before uh the problem is again you have too much dopamine in the brain you start having more side effects So again it's a double-edged sword The point is that this is typically an adjunct agent to patients who have been failing you know other drug therapy leodopa carbodopa maybe have already even tried dopamine receptor agonist Uh these are not usually a first or second line drug in most cases Um so intacapone is the one that's loed a little bit more Um and so it works only in the periphery right Not in the central nervous system you get all the same sort of side effects that is uh you know here Now they do report discoloration of body fluids um as one of the one of the sort of things you might see that's a little bit different than you know what you saw uh risk for melanoma Yeah I'm not sure about that but um again it's been listed in the product package insert Uh now if you do put them on patients who have leodopa you may need a reduction by 25% because again you're reducing the metabolism of it and so you got to find that balance Remember you'd rather air a little on the side of not enough and then titrate up uh for that reason Now you want to avoid monomine oxidase uh inhibitors uh and avoid their use because again you're really really going to prevent the breakdown of some of these dopamine nor epinephrine these kind of neurotransmitters and this can be problematic Now there is a small reduction in serum iron levels that they recommend you monitor those So risk of iron deficiency anemia um plus or minus okay toapone as I mentioned is because of its blackbox warning with uh causing fatal liver failure in at least a couple cases most patients uh we don't see this being used as much even though I think this one has a little bit longer of a halflife and duration but you have the same sort of side effects here and you need to reduce the dose if you were putting this on patients with leodopa ever since the warning came out Um if I'm not mistaken there really haven't been many cases of this So it's kind of questionable what happened early on Uh but maybe avoid these in patients with known liver disease or on other hippattoxic drugs You know give it consideration because obviously fatal liver disease is not a good outcome for a treatment Uh moving on to monomine oxidase inhibitors Okay So we have the historical agents recaguline salilene um so we these are drugs that work on monomine oxidase Now there's two types of monomine oxidase There's A and there's B So the older monominoidase inhibitors which tended to be non selective agents Okay Uh those were the ones that caused tyramine containing food issues hypertensive crisis all these other side effects and worries The drugs that we're talking about here are specific to blockade of monomine oxidase um uh specifically type B Okay Um and so that's why you see that listed out here Okay Type B So they work in the periphery as well as in the central nervous system to prevent the breakdown of dopamine but it's also preventing theoretically the breakdown of uh adinuric neurotransmitters as well or catakolamines right so recaguline azelt uh nice nicely dose for once a day as an adjunct to leodopa you can increase the dose a little bit it is a major 1 a2 substrate so it has the same drug drug interactions as I mentioned before where you have cypro amiotarone and um simetadine being inhibitors of 1 a2 there's not a long list of it thank god like 3a4 but definitely something that you want to um give consideration now given the fact that it still is a monomine oxidase inhibitor you want to be careful with its co-administration with other drugs that have other sort of serotonin or catakolamine like effects and so tramodol which inhibits the reuptake of norepinephrine and serotonin Uh obviously sleene would be dumb Why would you use two monomine oxidase inhibitors Uh maparidine because of its serotonin effects and lower ability to lower seizure threshold with its metabolite normine Tricyclic antidepressants are going to inhibit the reuptake of norepinephrine serotonin The point is watching out for these drugs Now it says here to stop uh before surgery by 14 days So about two weeks before an elective surgery they want you to stop these the drugs And the reason for that um is actually relevant So when you go to surgery many times they give you drugs that lower your blood pressure or they they have side effects that can be hypo cause hypotension Uh at the same time you're getting surgery where you can bleed And so if you have blood loss then you can also have hypotension And so many of times the anesthesiologist who's managing the vital signs and the induction of the patient while the surgeon is doing the procedure uh they're administering vasoactive medications including vasopressors So norepinephrine epinephrine phenylphrine and so they don't want any of these drugs sitting around in the body when they do that that would then cause an excessive rise in the blood pressure which can cause complications um in the surgery So that's why they want it gone from the system Um so this is a newer agent okay that's out there also for Parkinson's disease once a day Uh compared to recagulene and and sleene uh there's really to my knowledge really no significant uh difference Uh they do say that at doses less than 100 the interaction with tyramine containing products is probably low Uh again you these are not non selective agents they're selective for monine oxidase B uh eldipril here now this is important because sleilene is also used as a transdermal patch for the treatment of depression and that formulation is known as MSAM is its marketed brand name for the transdermal patch The the patch is not FDA approved for Parkinson's disease only or Zelipar is Zelopar is a oral disintegrating tablet formulation again be can be helpful for patients who are having trouble swallowing So remember that first onethird of the esophagus in the oral fairings is under skeletal muscle control or voluntary control and so you can force yourself to you know coordinated uh swallowing mechanism whereas once it gets down there then the autonomic nervous system takes over and so if you have trouble swallowing you don't want to aspirate and that's where transdermal patches ODT formulations can be helpful in some of these patients and so there's a few little pearls here that are important uh to recognize about brand names um formulations and dosing issues Now this one says stop 10 days before surgery whereas uh recaguline I think it was 10 days or 14 days You know the point being is one to two weeks You want to definitely be off and make sure the anesthesiologist is aware of this drug um in particular Make sure you obviously pull it off uh before they go into surgery Now remember there was that balance of the conergic system with the dopamineergic system that I mentioned And so triexifyadil or benzropene have been historically agents that have been sometimes added on to these regimens when the tremor is the biggest problem So where you have too much coneric activity and the dopamineergic properties that you tried to get from giving those drugs did not give the patient the maximum benefit of control that they were looking for But obviously those drugs with anticolinergic uh and anti-muscarinic uh ant uh properties can cause dry mouth blurry vision constipation and ur urinary retention Urinary retention is already a problem in some patients especially in patients with like BPH Um that can be a problem and then they need now fully catheter to pee You know I mean it's just this bad cycle And so this is where we're targeting the coneric neurons if we can't get sufficient dopamineergic inhibition there Okay And so we're trying to decrease the amount of acetyloline so that this raises up and creates more balance in that uh area Now there's some older agents uh that may augment the release and uptake of dopamine in the central nervous system So remember we've been talking about doing things that make dopamine inhibiting the metabolism of dopamine stimulating the receptors of dopamine and these are some older drugs that cause release and inhibit the re-uptake of um of dopamine Uh we don't use them as much anymore They have to be giving multiple times throughout the day We need to do renal dose adjustments Um and so they generally don't have uh they're not the drugs of choice in most patients So when we start dosing these patients on agents whatever class of drugs you end up starting to use on you will start to recognize wearing off effects So they have these on effects off effects is what we call them And that's where the diary can be very helpful at discerning when does the drug work cause too many problems or not enough control And so that's where you start making a dose adjustments where you increase the frequency or you change the dose and change the frequency or you go to a longer acting agent where we start to try to minimize the diskynesas and doniaas that can start to happen as a result of the peaks and the troughs the peaks and the troughs and only the time will tell being able to do that And so these are some of the things that you can do uh that I just mentioned here a second ago Okay All right So these are all listed here All right Now what about psychosis Because remember I said these patients start to have hallucinations They start having delirium They may even you know have psych other psychotic features and it's devastating to family and it and it's troubling even to the patient Um but they can have delirium which is sort of this altered state of consciousness It kind of waxes and wanes right They have disorganized thinking Like I said they can be hallucinating um you obviously want to treat the underlying cause because sometimes it's infection right changes in mental status sometimes it's other medications that's doing it and so you really want to give consideration but there is an antiscychotic that is approved uh pivot vancerin uh is uh FDA approved specifically for Parkinson's disease related or associated psychosis um and so it's just an atypical antiscychotic so it has dopamineergic antagonist activity and serotonin urgic modulation unfortunately is a major uh substrate of 3A4 and so they're subject to drug drug interactions and you have to consider lower doses or of that or dose adjustments in patients who have um drugs that are inhibitors of 3A4 especially strong inhibitors and then if they have severe you know chronic kidney disease where the crowding clearance is less than 30 then we need to you know back off but it's important to integrate other topics and know that the management of these patients is multiffactoral and not straightforward