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hey guys this is doctor joel. in thislecture i'm going to be talking about parkinson's disease. i'll cover theepidemiology, the etiology, pathology, some clinicalfindings, how to treat it, and then i'll finishoff with a couple of knowledge challenge questions just tosee where you're at. alright let's get started!so starting off with epidemiology it's useful to know the mean age of onsetwhich is 55 years old.. you may not be tested on thisspecifically, but as you approach clinical rotationsknowing the mean age of onset will help
you with your differentialwhen you have a patient who comes in with an essential tremor.. it effects malesabout same as females.. and its a very common disease the united states..as for etiology causes.. most cases of parkinson's diseaseare idiopathic however you aren't going to be tested on thatyou are going to be tested on more substantial causes.so for example, the first, 5 out of 5, mptp mptp is a neurotoxin and it causessymptoms of parkinson's disease because it kills the dopaminergicneurons in the substantia nigra. it was first discovered to have a link toparkinson's disease
in 1976 when a graduate student who wastrying to produce a drug similar to the opiatesproduced a substance with mptp as a major contaminantand injected himself with this drug and later developed parkinson's disease orsymptoms consistent with parkinson's. also, repeated head trauma, the primeexample of this is muhammad ali a famous boxer wholater in life to develop parkinson's disease.and lastly post encephalitic parkinsonism.which is the development of parkinsonism symptoms caused by a viral illness. so for examplethere was a strong
association with post encephaliticparkinsonism and the 1918 spanish flu pandemic.next, onto the pathology.. so histologically speaking, what are someimportant points that you need to know about this disease.?well, i've got two, both of them 5 out of 5..number one, you're going to see death of thedopaminergic neurons in the substantia nigra pars compacta.what does that mean?. let's break it down the substantia nigra is a brain structurefound in the midbrain. so in the picture on the right there's an inferiorupward looking view up the brain and
there's a transverseslice of the midbrain thats taken if we zoom in on those slices you can seeon the top up these two images the substantia nigra.which looks like a dark stain running throughthis portion a brain and in fact that makes sensesince the word substantia nigra means black substance. so there's thisblack line that runs through here and it'sstained black, or looks black because it had higher levelsneuromelanin which makes it appear dark. compare that to theslide or the transverse cut section
belowin a parkinson's patient. the color is almost all goneout of that section where the substation nigra isand that's because those cells have died. alright.point number two also 5025 lewy buddies lewy bodies are aggregation aboveinsoluble protein found within the nerve cells in patientswith parkinson's disease. they are eosinophilic, meaning that theystain a little bit darker red. and they'reusually round and pretty easy to pick up in ahigh-powered
field. next, into the physiologyof this disease so and as i said previously, the substantianigra has dopamine producing or dopaminergicneurons as those neurons or cells die,there is a decrease in the output of dopaminethus, less dopamine feeds to the stratum which means there's less of astimulation the basal ganglia which means there'smore of a inhibition at the motor pathways. sounds a littlebit complicated. let's look at it it will make more sense.okay this
is a coronal slice of the brain. it's notcompletely anatomically correct just because it'smore of a merging of an anterior slice and more of a posteriorslice together. but it's useful to draw it this wayjust in helping to describe parkinson's disease.we are interested in these structures herewhich i have color-coded and matched those colors with this box diagram on theright. so let's run through what we're looking atexactly. first the cortex, where the initiationof conscious movement begins. then that
we have certain basal ganglia structuresthe striatum which is yellow, the globus pallidus externus which isa lighter shade orange and the globus pallidusinternus which is a darker shade orange. next is the subthalamic nucleus, the thalamus. and lastly the substantia nigra with theletter should have purple being the substantia nigra parsreticulata and the bottom darker purplebeing the substantia nigra pars compacta. okay.so let's take what we've talked about, these anatomic structuresand build a normal
physiologic picture to talk about whatshould happen. and then we'll add the parkinson'sdisease on to it and show how parkinson's disease makesit go wrong. and to do this i'm going to use mostlythe box diagram on the right. i think this is a good pictureif you can draw this picture out for tests is pretty usefulbut not necessarily mandatory. okay. i don't think most few questions are gonnago into this depth also i should point out that there aremultiple neurotransmitters in the these pathways. but i'm not goingto be talking about different
transmitters.i'm just gonna be saying is it stimulatoryor is it inhibitory. and i'm going to use green arrowsif it stimulates something and read a redarrow if it. inhibits something alright first the substantia nigra pars compactait produces dopamine and it feeds that dopamineto the stratum when it gets to the stratumthe don't mean the same dopamine don't don't think that there's a differencethe dopamine the same dopamine axe on differentreceptors
different dopamine receptors. for twoseparate pathways and don't feel bad if you don't get this right away you mighthave to watch the video twice. that's okay. there's the indirect pathwayand the direct pathway. the indirect pathwayuses or has dopamine 2 receptors dopamine has a inhibitory effecton the cells that have those receptors. dopamine hasa stimulatory effect on the dopamine 1 receptors which the directpathway uses okay so so don't be confused by thatdopamine is produced dopamine is fed to the stratum there'stwo different
haves or pathways in the stratum andboth those pathways do different things with the samedopamine that it's given. alright firststarting at the cortex, a signal is sent that set for the cortex to stratumfrom the indirect pathway there is an inhibitory signalsent to the globus pallidus externus which then itself sends anotherinhibitory signal to the subthalamic nucleuswhich in turn since a stimulatory signal to the globus pallidus internuswhich then sends and inhibitory signal to the thalamusand then a stimulatory signal back to
the motorcontrol areas in the cortex. okay. little bit confusing, that's okay it'sokay, we'll get through it. now for the direct pathway. the directpathway. its a little bit simpler, which is why it'scalled the direct pathway. the direct pathway also sendsan inhibitory signal to the globus pallidusinternus and then it continues with anotherinhibitory signal to the thalamus. the thalamus sends an excited signal to thecortex and the movement is initiated. solet's play around with damage
or death of cells in the substantianigra pars compacta and see what happens toour signal for movementso if you remember back this is where the problem happens there'sdeath above the dopaminergic or dopamine producing cells in substantia nigraso as this picture illustrates the output decreases, and i'm gonna stayon the direct pathway to make it so i dont flip flop.there's a decrease excitatory signal to the direct pathway starting inthe stratum. because that direct pathway is notstimulated as much
its output decreases.so it decreases its inhibitory effect on the globus pallidus internus.well if the globus pallidus internus is notinhibited as much, it puts out a stronger signal, which is inhibitoryto the thalamus. that means that the thalamus is receivinga large inhibitory signal therefore its output is inhibitedits decreased. right. moving over to the indirect pathway. the indirect pathwayalso receives less dopamine however because these are dopamine 2receptors that means this pathway is notinhibited as much. therefore because it's
notinhibited as much it has a stronger signal come out. which happens tobe inhibitory. so it inhibits the globus pallidusexternus even more and then the globus is externusinhibits the subthalamic nucleus less the subthalamicnucleus stimulates the globus pallidusinternus more, and we're back to where we were.okay that makes sense if you put those two together those two pathways togetherthe ultimate result is it increase inhibition from the globuspallidus
internus and thus decreasedexcitation to the motor pathways from the thalamuswhich leads to the symptoms of parkinson's like bradykinesia anddifficulty initiating movements and slownessand rigidity. things like that okay. so now, does that last bullet point makesense now? decreased dopamine to the stratumleads to a decrease stimulation of the basal ganglia or stratum, whetherit be a decrease in the stimulation of the dopamine 2receptors or decrease in stimulation of thedopamine 1 receptors.
both pathways ultimately lead toand increase in the inhibition of the motor pathways. pretty cool huhand lastly just as a caveat. look there's a lot more to this systemthan i was able to explain the short amount of time. there's more pathwaysand also there's more transmitters at work here.so keep that in mind alright. let's move onnow on to the clinical findings in parkinson's disease.i like this picture, number one because i like muhammad ali.great guy he's done a lot for racial and religious freedom in the united statesbut he's also a well-known parkinson's
patient so. looking at our list the topthree things that you really should know about the symptoms of this diseaseare, number one, a pill- rolling tremor take a look at mister ali's hand hisleft hand here can you see with this thumb in thisfirst finger the motion the pill rolling tremor.you can just imagine it right there. also, look at his face.a mask like face, which just means it's difficult for him to make facialexpressions. like a smile. now another famousparkinson's patient michael j fox, also a great guy.notice how he also has a hard time
expressing his emotions through his face.parkinson's patients also have a certain kind of walk.you can almost tell parkinson's patients just by the walk.this picture is a great example of that. it's kinda hunched overshuffling of the feet, moving very slowly. oftentimes the blank stare otherthings that you'll hear of cogwheel rigidity which is acombination love being rigid and having tremors.very small shaky handwriting. posturalinstability and parkinson's patients also very often develop dementia.okay now into the treatments for
parkinson's disease.and i'm going to use this picture to help walkthrough how each drugworks. i think this is an awesome picture ifyou want download it there's a little there's a link on the right side therethat will help you find it. so what is this picture showing us? well,it's showing us a light purple colored nerve presynaptic nervethat is above a few light blue colour nerves.the purple nerve near the top is a different color because i wanted torepresent the sick system or those nerves that aredead or dying
or not functioning properly. essentiallynot making the dopamine from the substantia nigra as we talkedabout just a minute ago. okay, and then the the blue nerves downbelow are those ones that receive the dopamine.and they are not sick or dying. lets zoom inand take a look at levadopa & carbidopa. alright we knowthat we've got a problem with dopamine we're not making enough dopamine we'renot getting enough dopamine to where it needs tobe. so why don't we just give peopledopamine? why not just give them pills,
or give them a shot? well the reason isthat dopamine does not cross the blood-brain barrier.so if they took it by mouth or you give them a shot, it would neverreach the central nervous system and wouldnever do its job. the parkinson's symptoms would neverchange. so how do we get around that? well wegive leave a levodopa which is a shortened l-dopa in thepicture. l-dopa is able to cross the blood-brain barrier.and once it does it is able to be metabolize ortransformed or converted
into dopamine fairly easily through theenzyme dopa decarboxylase. perfectproblem solved right? well not really okay because this dopa decarboxylaseenzyme exists and works outside of the centralnervous system as well. which means that it would be producingdopamine in the peripheral body as well. and thatwill lead to a whole bunch of side effects, nauseadyskinesia. it would make you feel not very good at all.so to fix that carbidopa. carbidopa is a dopa decarboxylaseinhibitor.
it cannot cross the blood-brain barrier.thus, the peripheral conversion other l-dopainto dopamine is slowed a little bit, thus the sideeffects are decreased without changing themetabolism in the central nervous system. also, ithas another benefit, not only does it decrease the side effectsbut also allows more l-dopa to be available to be used in thecentral nervous system because it isn't converted peripherally.it's not wasted peripherally. okay along those same lines the comtinhibitors.
comt stands forcatechol-o-methyl transferase, it's another inside degrades ormetabolizes l-dopa (and dopamine) so, thus giving acomt inhibitor again decreases the waist and allowsmore l-dopa to be used where it's needed. and there'sto there entacapone and tolcapone. and outof those two drugs, you probably should knowthat tocapone is able to cross the blood-brain barrierhowever it has the side effect of possible liver damage.on the other hand entacapone cannot
cross the blood-brain barrierbut has less severe side effects. profileso next, the dopamine agonists. the dopamine agonistswork by directly stimulating the dopamine receptors that are on thehealthy nerves that are kinda starved for attention.those receptors that aren't being stimulatedby dopamine because there's obviously less dopamine available.so we're kind of bypassing that dopamine system and just directly hitting thereceptors with these medicines pergolide, bromocriptineropinirole and pramipexole all are
great examples of those.next on the list, again three out of five, the monoamine oxidaseb inhibitors. selegiline and rasagiline.the enzyme monoamine oxidase b is another enzyme that degrades andbreaks down dopamine. thus leading to a wasteof that transmitter that we're so desperately trying to hold onto.so if we inhibit that enzyme we're increasing the amount of dopaminein the system. and the last drug that i'll talk aboutis amantadine. now i'm amantadine isn't really an important drug clinicallyspeaking, for the management of
parkinson's disease.but i'm giving a three out of five because it's pretty important for yourtests. amantadine is used mostly as ananti-viral agent but also has a little bit of use in parkinson's diseasewhere it acts to decrease the re-uptake and also increase the release dopamine.so putting those two things together there's an increase concentration in thesynaptic gap okay so again, important for test-takingfor tricky questions. but not really important clinicallythere's just better drugs to manage the disease. alrightso i hope that makes sense. this has not
beenan in-depth review of these drugs. if you need anin-depth review, of these classes or these families of drugsyou need to look those up specifically and i'll covermore detail about the mechanism of action and side effectscontraindications and things like that. okay let's move on.alright my favorite part of the lecture.the knowledge challenge. my opportunity to pimp.okay first question. lewy bodies are what?well, think about the picture. are they
basophilic or eosinophilic?they are eosionophilic. next, what are they made of?well, they're aggregated protein. primarily alpha-synuclein. and lastlyintracellular or extracellular? okay good job! hopefully that was the answeryou picked! knowledge challengenumber 2, which of the following enzymes is inhibited by carbidopa?dopa decarboxylase. why was that important? well, the inhibitionof dopa decarboxylase means that there isless metabolism l-dopa into dopamine in the periphery. and thiscuts down on the side effects of
peripheral dopamineand also increases the availability of l-dopafor the central nervous system. okay what about to the last 2? i just madeup the first one. dopamine decarboxylase doesn'texist. what about catechol-o-methyl transferase? give me two examples of drugs thatinhibit that enzyme. i think about theamerican gangster al capone when i try to rememberthese drugs and how to pronounce them. entacaponeand tolcapone. and they're important becausethey can work the same way as
carbidopathey decrease the peripheral metabolism of l-dopa thus allowing more a bit to beavailable to do its job in the central nervoussystem. and lastly, monoamine oxidase b. give me twoexamples of drugs that may inhibit that. how aboutselegiline and rasagiline. again same kinda theorywere preventing the breakdown of dopamineso there's more available to do its job. good job you survived the pimpsession! hey guys, thanks forwatching this lecture. i had fun making it.
gimmea like, subscribe, please leave me a comment. i lovecomments. and feel free to check out any of these linksfor additional study helps. alright good luck in school!
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