DIP Episode 38 - Neuro Pharmacology Part 1

Okay, welcome. My name is divine. I am a PGOI one resident. I finished med school a few weeks ago and today's episode this is actually episode 38 of the divine intervention podcasts We're talking about neuro pharmacology. There is absolutely no way I can do this in one podcast to prevent brain overload, so I'm going to break this up into a bunch of podcasts But this is very high. But this is usually like a sore topic for many people So I will try to give you as much background as possible to meet the material a lot more digestible So just follow me along for the ride and hopefully by the end of these series of podcasts you become an expert at neuro pharmacology Which unfortunately is very high your first step one and step two So We'll do some pathophys first, right? So let's talk about Parkinson's disease.

I remember Parkinson's disease classically is associated with the resting tremor Okay, and in general it's associated with the degeneration of the Substance nigra which is a part of the midbrain Basically you have a build-off of Alpha Cineucline and that can form Louis bodies So classically in Parkinson's disease you find Louis bodies just in the midbrain Versus Louis body dementia where you find Louis bodies in more cortical structures like the Cerebral cortex itself now contrast the resting tremors of Parkinson's disease with the intention tremors that are associated with dysfunction of the cerebellum and Since we're going to be doing a lot of talk about the bizzle gangria I guess I may just go ahead and spend some more time around those structures Don't forget we have something known as the anterior limb of the internal capsule That classically separates the codic nucleus from the putteam it remember the codic is what degenerates and hauntings disease And don't forget that the strighetum is the combination of the codic And the putteamin and those two structures are separated by the anterior limb of the internal capsule And then there's the lentiform nucleus which classically describes describes the combination of the putteamin and the global spallidus Now there's also this special artery, right? It sounds like lentiform.

It's the lenticular stride artery It's actually a branch of the middle cerebral artery The thing is this artery actually supplies the posterior limb of the internal capsule And it so happens that the codicospinal tractone it's descent from the cerebral cortex down to the spinal cord All those fibers crowd in the posterior limb of the internal capsule And that limb is again supplied by the lenticular stride artery So if you have a lenticular stride artery in function you basically infarct the posterior limb of the internal capsule And the patient can have a contralateral hemiparesis, right? So they'll have contralateral opamuronurum problems Now because of this dysfunction of the codicospinal tract Now if you look at some midbrain anatomy right? So this is me just being as descriptive as possible If you look at the posterior midbrain right there's the superior collectulus Remember it controls vision right? And if you lesion this structure Those people tend to get a verticala deplopia And remember that the pineal gland is located superior to the superior collectulus So it's right above right? So if you have a pineyloma Right? You can cause something on a spary note syndrome Well, you basically have compression of the superior collectulus Which again can present as vesicular deplopia That's super high up to know for many exams And then remember below the superior collectulus we have the inferior collectulus right?

That deals with our audition and hear it Now there's also the cerebral aqueduct in the midbrain Okay, around this ear we have the adenjo-sphonucleus Which contains the cell bodies of the preganglionic parasympathetic fibers of crinonor III And then there's the reducleus It's just posterior to the substantiate nigra that sort of controls the I believe the reticulospinal tract And then there's the substantiate nigra right?

And then there's the parasympathetic part of the reticulospinal tract And then if you look anteriorly in the midbrain we have the cerebral pedoncles Not cerebral pedoncles There's a big difference between the cerebral pedoncles and the cerebral pedoncles The cerebral pedoncles are the things that are found anteriorly in the midbrain The space between those cerebral pedoncles is known as the intrapedoncular fossa And that's actually transmits crinonor III the oculumuronerv Now if we look at the pathways of the basal ganglion So there's the direct pathway And basically the big picture thing you want to understand here is that If you stimulate the direct pathway you'll actually promote movement And this direct pathway contains dopamine d1 receptors These d1 receptors the act on the direct pathway And it so happens that they are gs-copote Okay so this stimulates and denulates cyclids And basically the normal with this pathway works is that the stradum releases GABA Okay so I'm just discussing the normal function of the pathway And then we'll talk about how you could be modulated So the stradum releases GABA And that GABA then acts on GPI And GPI's normal job is to also release GABA Okay and in GPI releases GABA It inhibits the VA and VL thalamic nuclei And then if you inhibit the VA VL thalamic nuclei Normally these VA VL thalamic nuclei actually release glutamate To stimulate the motor cortex So let's assume you stimulate the pathway right So let's assume you stimulate the stradum You have an increased release of GABA Onto GPI Okay And if GABA is touching GPI more You'll have decreased activation of GPI So there will be a decreased release of GABA from GPI And if you have a decreased release of GABA from GPI You have an increased release of glutamate From VA VL thalamic Because they're being inhibited less And in so doing you then have a stimulation of the motor cortex A

nd you promote movement However, for the indirect pathway if you stimulate it You actually inhibit movement And it so happens that as against the D1 dopamir receptors That are found in the direct pathway We have D2 dopamir receptors in the indirect pathway Okay And these D2 receptors actually GI coupled Remember that Matto's numonic We talked about with respect to the autonomic pharmacology podcasts Now there are also most chrernic receptors in this indirect pathway They have the M4 most chrernic receptors I'll say these are probably lower yield to know But I'll just give you some quick information on them These M4 most chrernic receptors they are GI coupled So they inhibit a denylocyclease And it so happens that acetylcholine acts on these receptors Right because again some most chrernic receptors So basically acetylcholine through most chrernic M4 receptors Actually stimulates the indirect pathway So you may say come on divine, come on that doesn't make any sense How stimulating a GI coupled receptor Cause how would activation of a GI coupled receptor Stimulate the pathway The thing is At least my preliminary reading and my study of the literature Basically at least the Clifch notes thing that I got from All my reading is that When you activate these most chrernic M4 receptors You actually inhibit dopaminergic transmission In the basal ganglia Okay so by inhibiting dopaminergic transmission in the basal ganglia Dopamine no longer through detour receptors Inhibits the indirect pathway So because you have less dopamine inhibition Of the indirect pathway You have a net activation of the indirect pathway Now so how does this indirect pathway normally work Before we talk about what happens if you stimulate it This indirect pathway the stratum again releases GABA Okay, but the first point of call of that GABA from the stratum is no longer GPI As we had in the direct pathw

ay It's a Philly GPE The external globus pallidus network Okay so GPE So the stratum releases GABA And that acts on GPE Normally GPE also releases GABA Okay And that GABA from GPE talks to the subthalamic nucleus Okay the subthalamic nucleus it's normal job It's to release glutamate Okay and that glutamate it releases It's supposed to go to GPI The globus pallidus internal segment Okay that releases and that the normal job of GPI It's normal job as we mentioned for the direct pathway It's to release GABA Okay and then that GABA should act on the VAVL phalamus But the normal job Again I'm just describing normal jobs of these things I'm not talking about like oh if you release GABA This is what happened to this I'm just saying all like GPI releases GABA That's its normal job VAVL phalamus releases glutamate That's its normal job Okay and as VAVL phalamus releases glutamate That's supposed to act on the modal cortex And Modulate movement in some way shape or form So now let's take the scenario Let's assume you stimulate the stratum Okay in this indirect pathway You have an increased release of GABA onto GPI If there's more GABA being doused on GPI Right you'll have more inhibition of GPI So GPI's normal job of releasing GABA Will be decreased Okay because it's being inhibited So when you have less release of GABA from GPI Right You have less inhibition of the sub thalamic nucleus And if the sub thalamic nucleus is not inhibited as much You do its job better You release more glutamate And that glutamate acts on GPI Okay and because glutamate is an excitatory neurotransmitter By activating GPI GPI does its job even better So GPI then releases more GABA And that GABA that is In released from GPI Then inhibits The VAVL phalamus And the VAVL phalamus If it doesn't work any more It doesn't release glutamate And if it doesn't release glutamate You have less activation of the mo

tor cortex So that causes an inhibition of movement So again If you stimulate the direct pathway You promote movement If you stimulate the indirect pathway You inhibit movement And again you may see Oh divine how do I remember all the circuitry Because believe it or not You do need to know the circuitry for step one at least And occasionally some Bizarre step two slash neural shaft questions But basically one big thing you want to remember here Is that you may say How do I keep all these thin strips The way to keep it straight is Just remember that all these connections In the basal ganglia work with GABA With two exceptions The subthalamic nucleus Releases glutamate And the VAVL nuclei of the phalamus Also release glutamate Okay Whatever other thing releases GABA And I will just go ahead and mention this right now This is something more attuned to a neural shelf But if a person has carbon monoxide poisoning On imaging On a like MR imaging You'll find like hyperintens lesions In the global spalinus It's just one of those bizarre sensations You just want to memorize for the future Now Let's talk about Parkinson's disease So in Parkinson's disease You have a destruction Of the substantial nigra parts compact that Or let's say substantial nigra And if you destroy the substantial nigra Which produces dopamine You have decreased dopamine And if you have decreased dopamine You have decreased activity of the indirect of the Sorry Excuse me You have decreased activity of the direct pathway And you have increased activity of the indirect pathway So decreased direct Those these match Increased indirect Those eyes match And basically if you know that that's the pathophysiology Right for treatment The things you want to do is you want to increase dopamine But you also want to decrease acetylcholine Okay And I'll just go ahead and give you A trick Just think of it as an equation T

hat should help you with a lot of pharmacology I believe I've mentioned this in past podcasts Whenever dopamine is high Acetylcholine will be low Whenever acetylcholine is low Dopamine will be high Basically there is always Just take it from me It's not always true But it's accurate for usmlex There is always an inverse relationship between dopamine and acetylcholine So in Parkinson's disease There is low dopamine Because there is low dopamine There will be High acetylcholine There will be high acetylcholine So We want to attack those two problems in Parkinson's We want to increase dopamine Because dopamine is decreased in Parkinson's And we want to decrease acetylcholine Because acetylcholine is increased in Parkinson's disease Because by decrease in acetylcholine We will have less stimulation of the indirect pathway And we would not inhibit movement as much Because Parkinson's is a high pochkinetic disorder Now some other things I'll talk about I'll just talk about a few more diseases Before we then go into the pharmacology Right Myotonic dystrophy is another classic neurodyszee Basically it's myotonic So the kids tend to be hypertonic Although This is where they would try to trick you on exams It's a hypertonic disorder So it increases muscle tone But this kids usually when they are born They actually have a hypotonic So don't let that dissuade you on exams And this disease is classically Inherithic from mom And it's an autosomodominant disorder It's associated with trinocleothed repeats So CTG trinocleothed repeats So that means it must demonstrate the genetic principles of anticipation So where it shows up earlier in later off spring Or you have increased severity As generations are sure Because the trinocleothed repeats keep increasing And the classic exam description for myotonic dystrophy is Mom brings a kid to the hospital Mom shakes physician And it's hard f

or the physician To get his hand out of mom's hand Because mom is hypertonic So just a classic exam presentation To keep in mind And I'll just highlight this principle here That most trinocleothed repeat disorders Actually in herithedin an autosomodominant fashion Although there are two high-yield exceptions You want to know for your USML exams The first exception is fragile exendrum Frigial exendrum is actually in herithedin an X-linked dominant fashion I remember the trinocleothed repeat There is the CGG repeats And then there is fragile exetaxia Fragile exetaxia is actually in herithedin an autosomod recessive fashion And the trinocleothed repeats are GAA repeats Next disease I'll talk about is haunting tins disease So in haunting tins disease You destroy the cordate So the apparent size of the lateral ventricles On imaging Actually increases That phenomenon is known as a hydrocephalosa Ex-vacuum And This is a shaky explanation But it will make understanding haunting tins much easier on you Basically in haunting tins you initially Initially Initially You destroy neurons in the indirect pathway Okay So you have a selective destruction of neurons In the indirect pathway of the basal ganglia In haunting tins disease Okay So if you destroy the indirect pathway You are destroying an inhibitor of movement So that's why overall haunting tins disease is a Hyper-kinetic disorder Okay So remember I said parking tins is a Hyper-kinetic disorder So it's associated with decreased dopamine Hunting tins disease on the other hand Is a hyper-kinetic disorder So it's associated with increased dopamine Okay So you already know that if you want that to treat haunting tins You'd want to dumb down the effect of dopamine Although ultimately Hunting tins becomes a Hyper-kinetic disorder Because you ultimately end up destroying a lot more of your basal ganglia Both the indirect and the dir

ect pathways But You initially destroy the indirect pathway selectively So you have the direct pathway running in a mock So you have hyper-kinesis In early haunting tins disease And that's what you want to take away for exams Now remember in haunting tins disease They tend to have peripheral movements Almost always a guy in his 40s And the trinocrythide repeats as C-A-G trinocrythide repeats Don't forget your genetic anticipation Okay And don't forget that you want to decrease dopamine To help inhibit some movement Because it's a hyper-kinetic disorder Now next the disease I want to talk about is hemibalismus Hemibalismus arises from a lesion to the subthalamic nucleus Okay And again Walk with me here In the indirect pathway Right?

Remember that if If you release lesgaba from GPI Right? The subthalamic nucleus will be activated more Right?

Because GPI talks to the subthalamic nucleus If lesgaba is released from GPI There will be less inhibition of the subthalamic nucleus And you release more glutamate from the subthalamic nucleus If you release more glutamate from the subthalamic nucleus Uh Let's see Hope I'm not confusing myself here Okay So your release more glutamate from the subthalamic nucleus That will activate GPI some more If you activate GPI some more You'll have more release of GABA from GPI If you release more GABA from GPI Then you'll inhibit VAVL The VAVL nuclear of the thalamus more And if inhibits those more Then you will um You'll You'll not activate the motor cortex as much And you will inhibit movement So think about it If you lesion the subthalamic nucleus Which is what happens in hemibalismus If you lesion the subthalamic nucleus You have less release of glutamate From the subthalamic nucleus You have Because you have less release of glutamate You have less activation of GPI If you have less activation of GPI It won't do its job as well And its normal job is to release GABA So because you have less activation of GPI You have a decrease to release of GABA from GPI And if there's less GABA being released from GPI Then you have less inhibition Of the VAVL nuclear of the thalamus And if you have less inhibition of the VAVL nuclear of the thalamus You'll have more So you activate the motor cortex And you'll promote movement This is why hemibalismus is a hyper-kinetic disorder So the person has flailing of the arms And remember if a person has a lesion of the subthalamic nucleus on one side You have the flailing of the arms on the contralateral side So it's a contralateral disorder So hemibalismus in the right hand Is the right hand Usually due to a left subthalamic nucleus lesion I know you may say how to find your spending so much time on this But if you understand these diseases The pha

rmacology makes like plenty sense Okay and I'll just point you to the differential for peripheral movement So you want to think about hemibalismus You want to think about groupase trap Okay remember in groupase trap There's the Jones criteria, the major criteria The S distance for ceiling hamstrings And the other side is the same And the other side is the same And the other side is the same The S distance for ceiling hamstrings That's a choriform disorder With rheumatic fever And then haunting disease is also associated with choriform movement Remember it's a hyper-kinetic disorder And then will since disease can also present with choriform movement on exams Okay remember it's a secondary to an ATP7 B genutitio Now next thing I'll talk about is a phenylalanine metabolism Okay so phenylalanine is an essential amino acid Okay it's an essential amino acid We need to get it from the diet So how is phenylalanine metabolized?

The thing is phenylalanine first off Via the enzyme of phenylalanine hydroxylis It can be converted to tyrosine Okay so the other hydroxyl group to phenylalanine It becomes tyrosine Okay and it so happens that the co-factor for this reaction is BH4 tetrahydro biobterin Okay but the thing is when this reaction is done Okay you've used up the tetrahydro biobterin BH4 it's converted to BH2 Okay BH2 So the thing is if you want the reaction to keep going That BH2 has to be re-converted back to BH4 Okay and it's re-converted BH2 to BH4 BH4 is the co-factor for phenylalanine hydroxylis The enzyme that converts BH2 to BH4 Is an enzyme known as tetrahydro biobterin Reductase, okay?

So if you know all these details And you already know that all PKU arises from a deficiency of phenylalanine hydroxylis It should also be able to infer That if a person has a tetrahydro biobterin reductase Deficiency They could also present with a PKU phenotype Okay believe it or not That shows up pretty commonly on exams So PKU can be caused by two things It can be caused by a phenylalanine hydroxylis Deficiency or tetrahydro biobterin Reductase, deficiency Because you're not re-converting BH2 to BH4 And BH4 is a co-factor for phenylalanine hydroxylis Which converts phenylalanine to tyrosine Now tyrosine can then be converted by tyrosine hydroxylis to Dopa Okay Dopa stands for die hydroxy phenylalanine Remember phenylalanine hydroxylis Is a phenylalanine hydroxylis Dopa stands for die hydroxy phenylalanine Remember phenylalanine Phenylalanine hydroxylis Adds the first hydroxy group So you make tyrosine And then you add another hydroxyl group With tyrosine hydroxylis Okay to make Dopa So Dopa is just a phenylalanine with two hydroxy groups That's why it's called die hydroxy phenylalanine Now Dopa So continue that Dopa story in a bit But don't forget that tyrosine can also be converted by an enzyme known as tyrosine oxidase Some people call it tyrosinease To melanin Okay and this is actually the enzyme that's deficient in albinism So the person has a tyrosinease or tyrosine oxidase The efficiency they can have an albinism Now Dopa can be converted by an enzyme known as Dopa decarboxylase To Dopa mean So if you want to convert Dopa to Dopa mean You need an enzyme known as Dopa decarboxylase And this Dopa decarboxylase uses vitamin B6 Or pyrodoxyl phosphate as a cofactor Now please don't mix this up Let's just do a quick throwback to biochemistry The thing is vitamin B7 or biotin Is used as a cofactor by carboxylase enzymes So carboxylase enzymes use vitamin B6 Sorry use

vitamin B7 as a cofactor Remember carboxylase enzymes have repeated this I believe in a previous podcast Carboxylase enzymes are ABC enzymes They use ATP, that's the A They use biotin, that's vitamin B7 Remember you can have a deficiency of that If you take too many egg whites with an avidin And then the C stands for CO2 So carboxylase uses vitamin B7 or biotin as a cofactor On the other hand, D carboxylase uses vitamin B6 as a cofactor So don't mix that up on your exam, B6 D carboxylase B7 carboxylase Now Dopa mean is then ultimately converted by Dopa mean beta hydroxylase To Norepinephrine Can be converted to epinephrine in the adrenaline of the dollar But enzyme known as PNMT I believe that stands for phenol ethenolamine N-method transferase And the thing is PNMT actually uses cofactor known as SAM It uses SAM as a cofactor S adenosyl methanion Remember, S adenosyl methanion is a methyl carrier in the body I don't think I've talked about folate metabolism In any of these podcasts, it's like super super high you to know for step one I'll probably talk about it sometime in the future Okay, and PNMT is actually activated by cortisol So this is one of the ways cortisol has a permissive effect on the sympathetic nervous system And again, remember that this conversion from Norepinephrine I should drink some water So this conversion from Norepinephrine to epinephrine happens only in the adrenaline of the dollar Okay, again, under the action of PNMT Which is SAM as a cofactor Now, just the other thing here is that glutamate can actually be converted to GABA Remember glutamate is an excitatory neurotransmitter GABA is an inhibitory neurotransmitter Glutamate can be converted to GABA But an enzyme known as glutamate decarboxylase So because it's decarboxylase enzyme You already know that it should use vitamin B6 as a cofactor Now, don't forget that isoniasid can actually de

plete vitamin B6 Okay, so you are not able to convert glutamate to GABA Okay, and because you have too much glutamate on board You can actually have seizures That's part of the mechanism behind isoniasid causing seizures And don't forget that autoantibodies against the glutamate decarboxylase I'm associated with type 1 diabetes Just one of those things we expected to know for exams So now we've talked about a lot of pathophysiology Let's then go into the pharmacology Okay, you'll see again, this will be a lot easier to understand Now that the pathophys and pathology has been discussed So let's talk about the treatment of Parkinson's disease Okay, so we know in Parkinson's disease we have low dopamine The problem is you cannot give people straight dopamine Because dopamine has no ability to cross the blood-brain barrier Okay, so you want to give a precursor to dopamine in this case, dopamine Dopadol has the ability to cross the blood-brain barrier So Parkinson's disease is classically treated with a drug known as Livodopa Livodopa is a dopamine analog It crosses the blood-brain barrier It's then converted to dopamine in the brain Via dopamine decarboxylase Okay, and then you relieve the symptoms of Parkinson's But there's a small problem with that Okay, the thing is, just like there's dopamine decarboxylase in the brain There's also dopamine decarboxylase in the vasculature Okay, and in the periphery if you make, so basically like not the brain And that dopamine decarboxylase in the periphery Also can convert the dopamine And that dopamine has some visual dietary effects It can cause a lot of problems like vomiting, an nausea, diarrhea And hypertension and all that stuff We don't want that So when a person is getting Livodopa for Parkinson's We try to give them something that can inhibit that peripheral dopamine decarboxylase Okay, and it so happens that that drug is a

carbidopa Okay, carbidopa is an inhibitor of dopamine decarboxylase But there's one more high-eof thing you want to know about carbidopa Carbidopa is actually a non-competitive inhibitor of dopamine decarboxylase Okay, so if you're thinking in terms of Mikaelis mentine kinetics You have no change in KM, okay?

But your VMAX is decreased, okay? That's how carbidopa works It's a non-competitive inhibitor of dopamine decarboxylase Now, another enzyme, COMT, a cathacol-O-Methyl transferase It can actually break down dopamine to compound known as 3 OMD 3 OMD I think is like 3 hydroxy-method dopamine or whatever Just remember 3 OMD, okay? I think it's 3 O Methyl-Doparkyl, but 3 OMD that's good for our purposes So 3 OMD, the thing is it has two special properties One is that 3 OMD is a partial agonist at dopamine receptors Okay, it's a partial agonist at dopamine receptors Why am I harping about this? If you have something that acts as a partial agonist at a given receptor If the full agonist were around, you'll get the full effect of the... If you didn't have the partial agonist around And the full agonist just did its job, you'll get full effect But this partial agonist is giving you less than full effect, okay? So a partial agonist at a given receptor functionally works as an antagonist at that receptor So if you remember from the...

autonomic pharmacology podcast Where I talked about drugs like acybutolol and pindolol Acybutolol and pindolol are partial beta receptor agonists But we classify them as antagonists because they are basically taking the place that could have been taken By a full agonist for you to get full effect from activation of that receptor So that's the same concept here 3 OMD is a partial agonist at dopamine receptors And you get 3 OMD by comt-t converting dopamine to 3 OMD So comt-t, categorical, or methyl transfer is can convert dopamine to 3 OMD So 3 OMD I said it has two special properties One property is that it's a partial dopamine receptor agonist So it's functionally a dopamine receptor antagonist And then the second thing is that 3 OMD actually competes with Dopa for entry into the central nervous system So if you have high levels of 3 OMD Dopa actually has a very hard time getting into the central nervous system crossing the blood brain barrier So we can basically see I'm hopefully setting you up for this realization That having 3 OMD around is not a good thing And we know that comt-t is the enzyme that makes 3 OMD So if you want to treat Parkinson's and we know that 3 OMD is bad You want to go ahead and inhibit comt-t You want to go ahead and inhibit comt-t Now the drugs that inhibit comt-t are the capone drugs They are the capone drugs One is known as entacapone The other one is known as tokapone So let me make some distinctions between entacapone and tokapone Tokapone So you may read in some literature and by that I'm saying basically for a state That this one works only in the brain This one works in the brain and the periphery Let me give you what I believe is correct from my review of the literature And a lot of pharmacology and material The thing is entacapone and tokapone both work in the brain and in the periphery Entacapone and tokapone both work in the brain and in the periphery Now what are the differences between these drugs that may be tested?

The thing is tokapone, right? So I said it works in the brain and periphery The only thing is that tokapone is actually a lot better than entacapone at crossing the blood brain barrier So because tokapone is amazing at crossing the blood brain barrier You may think, oh yeah, so this should be the preferred agent, it's not Because the thing is tokapone is hepatotoxic So it's great at crossing the blood brain barrier but it's hepatotoxic That's why entacapone is used more commonly Entacapone also works in the brain and periphery It's not as good as tokapone at crossing the blood brain barrier But it does not have the hepatotoxicity that's associated with tokapone So between tokapone and entacapone, entacapone is classically preferred Now one other thing I want to talk about is monamine oxidase B, okay?

M-A-O-B The thing is M-A-O-B breaks dopamine down into inactive metabolites It's even more specific for dopamine than M-A-O-A So the thing is if you wanted to treat Parkinson's You wouldn't want to break down the dopamine you have that's already in inactive supply So you want to go ahead and inhibit an enzyme that breaks down dopamine like M-A-O-B And this is where your gillin drugs coming to play Drugs like cellulin and resagilin Cellulin is an M-A-O-B inhibitor The common side effect with cellulin is it causes insomnia, makes you feel crappy Because it so happens that cellulin is actually converted by some enzymes in the body to amphetamine And amphetamine is used to treat ADHD, right? So it increases focus and concentration So that should kind of make sense that it causes insomnia as a side effect, cellulin Because it can be metabolized to amphetamine Now, resagilin on the other hand It's more commonly prescribed than cellulin because it's not broken down to amphetamine Although it's I believe if I'm not mistaken, it's a little more expensive than cellulin But resagilin is a good drug relatively cleaner than cellulin Now, for Parkinson's, right?

So I've said you can give dopamine, you can inhibit, come to you, inhibit M-A-O-B Another thing you can do is you can give a straight-up like dopamine receptor agonist So you can give drugs like a primary pexol, ruptin-erol, cabergo-lin, bromo-cryptin I believe there are others like a rotigotin, epomorphine Those are all dopamine receptor agonists, okay? So primary pexol, ruptin-erol, cabergo-lin, bromo-cryptin, epomorphine, and rotigotin But I would say those last two are probably lower you to know Although I believe they're in first state if I'm not mistaken But these drugs though, right? So you could use them to treat Parkinson's but they're just a few things you want to keep in mind So the thing is there is an unoff phenomenon associated with many of the Parkinson's drugs If I take that back, not many of the Parkinson's drugs Specifically, carbidopa-livodopa, there's an unoff phenomenon with those drugs Those drugs, because they have that unoff phenomenon that can happen after you use those drugs for years Those drugs are not classically prescribed first for Parkinson's disease If I have for Parkinson's disease, the go-to medications initially At the dopamine receptor agonist, like these drugs I just mentioned, or a month a day, which I'll talk about in a bit So usually go to liver-dopa-carbidopa last in Parkinson's disease Because you're basically trying to bite time before that unoff phenomenon shows up So these dopamine agonists, right?

So let's say some more things about them, right? So these drugs, you want to remember that they can decrease your levels of prolactin Remember, another name for dopamine is prolactin inhibiting factor So if you're given a dopamine receptor agonist, you'll decrease the release of prolactin You're basically modulating the tuberum for developed pathway of dopamine So you can actually use these drugs to treat prolactinomas In fact, these drugs are the first line meds for the treatment of prolactinomas I have a patient who has prolactinoma on exams, this should be what you jump to first Now, the thing is, these drugs though, they can actually cause orthostatic hypertension Because like I mentioned earlier, dopamine actually has some visodilitri activity So if you give a dopamine receptor agonist, you can actually have a visodilitri These drugs, they can also cause constipation, okay? And they actually have the ability to activate the aeropostreamer So they can get a lot of like vomiting and a person can get a lot of vomiting and MSS with these drugs So this kind of explains why dopamine receptor antagonists like metoclopromide and donperidone Although donperidone is not used in the US, it is used in Europe But metoclopromide and donperidone, they can use them as prokinetics So increasing flux through your GI tract, right? So for example, an patient that has a gastroprasis, classically a diabetic And you can also use these drugs as an antimedics, right?

So like metoclopromide donperidone, you can use them as prokinetics and antimedics Because they are antagonized dopamine receptors That is why dopamine receptor agonists, which are the actual topic of this discussion Like Promethexol, Ropineroch, Arbegolimbromocryptin, cause constipation And they can cause a lot of vomiting and MSS Now these drugs can also cause a psychosis, okay? Because remember, if you have high levels of dopamine in the misolimbic pathway High levels of dopamine in the misolimbic pathway actually cause the positive symptoms of schizophrenia Of which psychosis is one, okay? So if you are given a dopamine receptor agonist, you are activating dopamine pathways in the misolimbic pathway And that can cause a psychosis as a side effect, okay?

That's why anticycotics are given to treat schizophrenia And please do not confuse the misolimbic pathway We are increased levels of dopamine associated with worsening of a person's positive symptoms With the misoccurricle pathway, we are increased levels of dopamine actually associated with much better Or I guess reduction, let's put it this way to make it simple Reduction in the negative symptoms of schizophrenia So again, high levels of dopamine in the misolimbic pathway are bad for schizophrenia They increase your positive symptoms High levels of dopamine in the misoccurricle pathway are good for schizophrenia They reduce the negative symptoms I will have a couple of podcasts on psych pharmacology In fact, I will probably bring those up after I'm done with neuro pharmacology Okay, and then last thing with these dopamine agonists You can actually use them to treat restless legs syndrome Remember, restless legs syndrome is classically associated with ion deficiency and emin Okay, now a mantidine was previously used to treat the flu, like the influenza virus I mentioned this in the antiviral podcast It's actually now used to treat Parkinson's, okay?

And there are multiple mechanisms here A mantidine actually increases the release of dopamine in the CNS It prevents the reoptic of dopamine And there are actually some literature out there that shows that it actually has some inhibition of monamine oxidase Okay, so all these things, both to dopamine levels, so you could potentially use this to treat Parkinson's Now, a big side effect you want to know the mantidine and probably with like your MEOB inhibitors is a levidoretic virus No one really knows why this is, but some weak explanations you may encounter is that By increasing dopamine energy activity, you get more visual dilation So you have like more extravacition of fluid, which gives the skin like a motto, like a net-like appearance But I don't believe that to be exactly true, so I'll just forget about that But just memorize this as much as it saddens my heart to say Just go ahead and memorize this fact toy that levidoreticularis is associated with a mantidine and your MEOB inhibitors Now, one thing I said that, one equation I gave you a few minutes ago is that high levels of dopamine will cause low levels of acetylcholine So if a patient has Parkinson's, they have low levels of dopamine So because they have low levels of dopamine, they will have high levels of acetylcholine And we said that acetylcholine is an activator of the indirect pathway So you want to dumb down the effects of acetylcholine as a treatment for Parkinson's disease So that's why you use drugs like benz-tropin and trihexifenedel Ben-tropin and trihexifenedel These are both mascarinic receptor antagonists that can be used for the treatment of Parkinson's disease Now remember that if a patient has schizophrenia and they are taken on neuroleptic Remember those neuroleptics are dopamine receptor antagonists?

So you are basically using pharmacological means to induce Parkinsonian features So extra pyramidal symptoms Because you are giving dopamine receptor antagonists in schizophrenia You can predict that your levels of acetylcholine will go up So you can actually use these drugs that have been stropping and trihexifenedel Which are mascarinic receptor antagonists as treatments for the extra pyramidal symptoms of neuroleptics So just I want to keep that in mind as well Now let me draw a quick parallel here to psychiatry This is why I love neuropharmacology so much You can integrate like a ton of stuff with neuropharm The thing is I just talked about MEOB inhibitors like cellulogenin or acetylene Remember in the treatment of depression you also have just generic MEO inhibitors These are drugs that inhibit both MEOA and MEOB MEOB is more specific for the breakdown of dopamine But MEOA breaks down dopamine, neuropinephrine and serotonin So these monamine oxidies inhibitors from psychiatry Which I will talk about in a different podcast Remember these are drugs like phenolcine Drugs like trinocyperamine And then there is another one here that is not so bad I believe it is isocarboxazid So these drugs, the thing is the parallel I wanted to draw here Is that you never want to combine, let's say a patient has depression And they have Parkinson's You don't want to give them an MEO inhibitor for the adipression And an MEOB inhibitor for their Parkinson's Because that can trigger what?

Serotonin syndrome Serotonin syndrome because you are giving too serotonergic agents if you make MEOB actually does have the ability to break down serotonin But to a very limited extent So if you combine these two things together, the person can have serotonin syndrome And classically it presents with fever It is more gradual onset and MEO clonus That is the classic buzzword for serotonin syndrome And how do you trace a serotonin syndrome? You want to go ahead and block serotonin receptors Classically with a drug known as C-pro-hypidin It is an anti-hystamine That actually has very powerful serotonin receptor blocking activity Although for serotonin syndrome you could also give a benzose So just so that you keep that in mind for the future In case you don't see C-pro-hypidin as an answer choice Now, don't forget your other drugs that are serotonin syndrome So like your triptants Your symmotriptan, zomy triptan, reza triptan Those are serotonin receptor agonists That are used to treat migraines Don't forget that in the isolate It is your 50th inhibitor of the P-site So it is an initiation inhibitor I talked about that in the antibiotic podcasts Remember, in Nasolid has some weak monamine oxidies in inhibition Activity, okay? So you can trigger serotonin syndrome SSRI's selective serotonin reoptic inhibitors And also trigger serotonin syndrome St.

John's warts In fact, it is actually used to treat mild to moderate depression Can also trigger serotonin syndrome Please do not forget that St. John's warts is also an activator Of the cytochrome is an inducer rather Of the cytochrome P450 system Okay? So you can increase the rate of metabolism of drugs Now, let's compare serotonin syndrome with malignant hypothermia Okay? Both present with fever Okay? But the thing is serotonin syndrome In fact, let me talk about my malignant hypothermia first Malignant hypothermia just like serotonin syndrome can present with fever Okay? But malignant hypothermia tends to have more of... I hope I'm not mixing this up Okay, I'll see something now And if it's wrong, I'll correct it in the next podcast But I'm pretty sure this is correct Malignant hypothermia tends to have more of a gradual onset Okay? Malignant hypothermia tends to have more of a gradual onset Serotonin syndrome tends to have more of... Wait... Huh? Hang on, hang on, hang on Serotonin syndrome, I believe, tends to have more of a gradual onset Malignant hypothermia, I believe, tends to have more of a rapid onset Okay? So malignant hypothermia, rapid onset Serotonin syndrome slow onset So the S is match Serotonin syndrome slow onset Malignant hypothermia rapid onset I'll look this up and clarify this in my next podcast Sorry, some of this stuff I'm seeing just straight from memory Okay So malignant hypothermia though The classic presentation is muscle rigidity Okay?

Serotonin syndrome could have more of a rigidity But that's like a very rare presentation Okay? So again, but the buzzword for serotonin syndrome is myoclonus Okay? So muscle rigidity is to malignant hypothermia As myoclonus is to serotonin syndrome And don't forget that malignant hypothermia can present similarly to a neuroleptic malignant syndrome Okay? Although the exposure is different, neuroleptic malignant syndrome is because you were exposed to an antipsychotic, okay? My ligandhyperturmit is because you were exposed to succinocholine Remember that's a depolarizing, your muscular blocking agent or um, what's the other thing? Or there's one other drug that can trigger that Or hallothene, hallothene is an inhale that is sterectin, essentially no one uses anymore Because it's hepato toxic Okay? So, uh, how do you treat malignant hypothermia? Right? You actually give denture link Remember denture link is a calcium channel blocker Okay? Uh, it's an inhibitor of the calcium channel which is the ryanidine receptor Remember the ryanidine receptor is in fact a calcium channel So denture link is actually a calcium channel blocker Okay? It's a calcium channel blocker Now, um, remember that malignant hypothermia Right? It's associated with autosomal dominant mutations Most commonly in the ryanidine receptor, okay?

So if you have that mutation, you have constant activation of muscles And if muscles are contracting too rapidly And for a sustained period, a lot of heat will be generated, right? So a prescient becomes a hypothermic Now, um, you could also have a mutation in the dihydroperidine receptor Uh, as the cause of malignant hypothermia And again, that's also in here, you think In an autosomal dominant fashion But the most common mutation is in the ryanidine receptor Now, let's then talk about haunting disease, okay? So haunting disease, um, haunting disease again Classically, for early hauntings, you have hyperchinesis, okay? There is increased dopaminergic activity in early haunting disease So you'd want to have an anti-dopaminergic effect If you want to treat hauntings So how can we do this? We can do this in a couple of ways, right? So we can give hollow peridol, okay? Remember, that's a dopamine receptor antagonist, okay? I remember there are many side effects with this Uh, you can increase prolactin levels Uh, so a patient can get like an acomastia, low libido, and all that stuff And it's due to the blockade of dopaminergic activity In the tuberoinformed developed pathway of dopamine Um, and just as an aside Let's just stick some quick dovetail into endocrinology Don't forget that hypothyroidism can also cause hyperprolactinemia Because if a person is hypothyroid, right?

Uh, the levels of TRH will go up And another name for TRH, if I'm not mistaken, is prolactin-releasing factor So if you have high levels of TRH, you release more prolactin And the patient will become hyperprolactinemic And they can get an acomastia, gallactorea, and low libido, okay? Now, um, going off of going along with a theme of trying to decrease dopamine in haunting tense Uh, there's a, there's a transport known as V-mat, okay? V-mat It actually packages dopamine into vesicles, okay? So if inhibited V-mat, dopamine will not be packaged into vesicles And it would not be released at the synapse, okay? That's how drugs like resurping Uh, and tetrabenazine work, they both inhibit V-mat Now for ALS, another disease I will talk about, I know this has gone kind of long enough, uh, we've done a very shortly Uh, but ALS, in myotrophic lateral sclerosis, also known as lugearic disease I remember, classically, these patients have both upper and lower moron neuron problems Because they're destroying the, uh, ventral horn of the spinal cord and also destroying the cortical spinal traps However, there are no sensory symptoms in ALS, okay?

And remember, it can be associated with an SOD1 mutation, a superoxide, dismutease mutation Remember, that's part of the oxidative burst in white blood cells Um, and one of the things they think on, uh, I guess the underlying pathophysiology at least, uh, that is thought to contribute to the presentation of ALS Is that you have something known as glutamate excitotoxicity, okay? Uh, just sort of think of it this way If you're too excited, you begin to do like crazy things, okay? So glutamate is an excitatory neurotransmitter, so it makes neurons do crazy things And if you do, imagine, let's say you're doing crazy things like breaking the speed limit and all that crap Let's assume a person could like have like an accident and like die, okay? So if you have too much glutamate, you have glutamate excitotoxicity that makes the neurons go like crazy and then they die, okay? So, uh, glutamate excitotoxicity is believed to be the primary cause of one of the big implicators in death of neurons in ALS So, uh, and it so happens that glutamate is an agonist at receptors known as NMDA receptors, okay? NMDA receptors Those receptors when you activate them, calcium comes into the cell, uh, magnesium can bind in the pocket and present, prevent that calcium from entry But that's, that's for a different podcast, but I'll just leave it at that So glutamate is an NMDA receptor agonist, okay?

So if you want to dumb down these glutamate excitotoxicity effects, you want to go ahead and inhibit those NMDA receptors, okay? So you give NMDA receptor antagonist like Ryluzol, okay? Ryluzol is used to treat Lou Gehrig's disease, okay? It's an NMDA receptor antagonist Now for Alzheimer's, right? Remember, in Alzheimer's, you can build up like hyperfossilithetal protein, you can have like, um, amyloid plaques, those are like the senile plaques Um, and you also have some glutamate excitotoxicity in Alzheimer's, okay? So you can actually give an NMDA receptor antagonist as well, um, for the treatment of Alzheimer's, okay? Uh, the drug here is Meman team, so please don't confuse Meman team, which is used for Alzheimer's with Ryluzol, which is used for Lou Gehrig's disease or ALS, okay? So Meman team, if you watch TV, there's this drug known as NMDA XR, that's Meman team, okay? It's an NMDA receptor antagonist that can be used to treat Alzheimer's Now, the thing is, in Alzheimer's disease, classically, you have low levels of acetylcholine, okay? So the thing you can try to do is you can try to boost your levels of acetylcholine as potential treatment for Alzheimer's disease. Uh, doesn't really help much, but it has some benefit, okay? According to studies. So, um, we know that acetylcholine esterase breaks down acetylcholine, okay? So that decreases your levels of acetylcholine.

So if you know that you want to increase your levels of acetylcholine, you want to give an acetylcholine esterase inhibitor, okay? In the treatment of Alzheimer's disease. So you give acetylcholine esterase inhibitors like dunepazel, galantamine, rivestigmin, and there's one more known as tachran, okay? So just remember, like, those are ganglion DRG since we're talking about neurod for dunepazel, R for rivestigmin and G for galantamine. And as an aside, um, don't forget that acetylcholine is made in the B-son nucleus of my nerd, okay? And it's made by an enzyme known as chat, okay? Choline acetylcholine transfer is talked about this in the auto-nomic pharmacology podcast. So in view of this, you may actually want to remember that the pathophysiology of Alzheimer's may involve this function of chat, okay? Choline acetylcholine transfer is, which is the right-limiting enzyme for acetylcholine synthesis, or this function of the B-son nucleus of my nerd, okay? These are both sources of acetylcholine. So if you have this function of those things, um, potentially, person could potentially have Alzheimer's. You may see, oh, to find this looks too loyal. Well, think again, believe it or not, it's one of those bizarre things you want to keep in your memory bank, for example. Now, to wrap up here, I'll just, since we've been saying so many things about the NMD receptor antagonists, I just figured I might as well just put everything together for you here.

So there are four high-yield NMD receptor antagonists you want to know for your exams. The first one is Ryluzol, used for Lugeria disease. I talked about that already. The second one is Meman team, used for Alzheimer's. Talked about that already. The third one is Dexromethorefen, okay? This is used when the realm of Pomonology, okay? So Dexromethorefen is a cough suppressant. It's actually a weak opioid, so you can reverse it with Naloxone, but it actually has NMD receptor antagonist activity. You can use it in the treatment of like cough. It's a cough suppressant. It's an anti-tosive medication. And then the last one is ketamine. ketamine is also an NMD receptor antagonist. It's a dissociative anesthetic, okay? It's used in anesthesia territory, okay? So that's all I'm going to say about the NMD receptor antagonists. I'll probably have a podcast, or part of a podcast, where I talk about anesthesia from ecology. So I know this was a lot, but please, please, please, please, please. The material in this podcast, super high-yield. I know you may say, I'll divine you, I always say, high-yield for everything, but I promise you, like these topics we've discussed are not low-yield. This podcast, we've talked about a lot of physiology, a lot of pathology, a lot of diseases, a lot of localization, a lot of pharmacology, some endocrinology, and some psychiatry. So just hopefully this puts a lot of things together for you.

I will continue this in our, continue on neuro-pharmacology in a different podcast. We'll probably start with the seizure medications. I wish all the best, have a wonderful day, and I really hope my dear wins are tomorrow. So have a wonderful day, and God bless. I'll see you in the next podcast.

Resting tremor, bradykinesia, and rigidity, due to degeneration of the substantia nigra.

Increased dopamine activity (due to selective destruction of the indirect pathway).

Deficiency of phenylalanine hydroxylase (or tetrahydrobiopterin reductase), leading to accumulation of phenylalanine.

Carbidopa, which is co-administered with levodopa.

GABA (Inhibitory) and Glutamate (Excitatory).

Mascarinic receptor antagonists (e.g., benztropine, trihexyphenidyl).

PD involves degeneration of the substantia nigra; HD selectively destroys neurons in the indirect pathway.

Dopamine decarboxylase (DDC); Vitamin B6 (Pyridoxal Phosphate).

The subthalamic nucleus (STN) and the VTA/VLA thalamic nuclei.

Carbidopa.

High levels of serotonergic agents (e.g., SSR Is, triptans), resulting in symptoms like myoclonus and altered mental status.

Dopamine agonists (e.g., bromocriptine).

Levodopa-induced dyskinesia (or levodopa-related complications); also, they can cause neuroleptic-like symptoms.

PD involves degeneration of the substantia nigra; HD selectively destroys neurons in the indirect pathway.

Dopamine decarboxylase (DDC); Vitamin B6 (Pyridoxal Phosphate).

The subthalamic nucleus (STN) and the VTA/VLA thalamic nuclei.

Carbidopa.

High levels of serotonergic agents (e.g., SSR Is, triptans), resulting in symptoms like myoclonus and altered mental status.

Dopamine agonists (e.g., bromocriptine).

Levodopa-induced dyskinesia (or levodopa-related complications); also, they can cause neuroleptic-like symptoms.