Transcript for:
Cholinergic Agonists (Parasympathomimetics)

what's up ninja nerds in this video today we're going to be talking about cholinergic agonists also known as paris and patmometics heck of a name but if you guys really want to understand this video you guys really want to get into this i suggest going down in the description box below we'll have a link to our website on our website we have some awesome notes we have some great illustrations that i want you guys to follow along with me also if you guys like this video you benefit from it it makes sense please support us by hitting that like button commenting down in the comment section but most importantly subscribe also check out our website we had a lot of cool things offered there all right let's start talking about the cholinergic agonist before we do that though we have to understand a little bit about the kind of cholinergic system if you will so we talk about the cholinergic system it's the system where the neurons are particularly releasing acetylcholine now but without us getting really really down the depths of this you guys can really if you want to understand a little bit more we have a video on cholinergic receptors and our autonomic nervous system where we go over this all the physiology in more detail for here we're going to break it down a little bit more simply what i want you guys to remember is when we talk about cholinergic pathways this is the i think the best in understanding the pharmacology aspect so we have a bunch of different cranial nerves and those cranial nerves particularly some of them have parasympathetic fibers and what i want you guys to remember is that these parasympathetic fibers innervate particular target organs some of those particularly cranial nerve three you know cranial nerve three supplies particularly like the the eye right so particularly like you have what's called the extraocular muscles well it even supplies some of the structures inside of the eye like the ciliaris and the pupil muscle so here we have a parasympathetic fiber that's supplying the pupil and you know what it actually does to the people that causes pupillary constriction that's a normal type of function but we give it a special name we like to be all bougie and stuff so we like to call it meiosis all right so plays around what's called meiosis which is basically a fancy word for pupillary constriction it also kind of moves the ciliaris muscle contracts it which also helps to be able to play a role with what's called accommodation which is kind of changes in our vision kind of like distances okay so it also plays a role in accommodation now the next thing is we also have another particular granola so we have cranial nerve three which is a parasympathetic nerve and it has cholinergic types of fibers the next one is particularly going to be cranial nerve seven so cranial nerve seven also known as the facial nerve also is going to be a nerve that goes and supplies our lacrimal glands and also supplies some of the salivary glands like the submandibular salivary glands of the lingua salivary gland and even some of the terrigo palatine glands as well but the whole point is is that it plays a role in what's called lacrimation right so the production of tears and it also plays a role in some of the salivation process okay so salivation now there's another nerve that also plays a role within salivation that's actually going to be the glossopharyngeal nerve so we'll have the glossopharyngeal nerve or cranial nerve nine and then we have another cranial nerve which we'll talk about called cranial nerve 10. but cranial nerve 9 also plays a role with salivation but primarily via what's called the parotic glands all right so the next thing that i want you guys to remember is we have created nerve ten which is the vagus nerve now the vagus nerve also has lots of cholinergic fibers that actually work particularly on some of our viscera such as the heart and when it works on the heart it acts as what's called a negative chronotropic agent so it helps to be able to slow down the conduction of the heart and we call that potentially when it's working on what's called the av node slowing down that conduction it'll basically decrease your heart rate so the one thing that you'll see with this one is what's called bradycardia now one of the things that we know is with us slowing down our heart rate we could potentially slow down our cardiac output because we know cardiac output is equal to heart rate time stroke volume so we can see both a decrease in heart rate and maybe a subsequent drop in our cardiac output so that's an important thing the next thing is also and innervates particularly the smooth muscle of our bronchioles and what it wants to do is when you have the smooth muscle of your bronchials generally the sympathetic nervous system you want them to dilate within the parasympathetic you want them to constrict so it'll actually induce what's called bronchoconstriction so it'll induce what's called broncho constriction so kind of make the actual airways a little bit smaller narrowing the amount of air getting in okay because you know when you're in the resting digesting kind of relaxing type of state you don't want to be utilizing a lot of energy and doing a lot of things so that's why we don't really need a ton of airflow when we're resting and digesting the next thing is our vagus nerve also helps to innervate parts of our git but on the upper parts of the git so the stomach the duodenum other parts there and it helps to be able to promote secretion so it actually helps to stimulate what's called hydrochloric acid production by the stomach and some of the secretions of particular molecules within the intestines so one of the things that we'll see is we'll see gi secretions but it also loves to cause the contraction of the smooth muscle of the git and so we'll see a lot of what's called increased motility of the git as well so peristalsis in the same way this is all of your cranial nerves yeah we have what's called the parasympathetic fibers from the sacral part of our spinal cord you know from generally like s2 to about s4 we'll have these parasympathetic fibers that can come from that part of the spinal cord and then go and deliver parasympathetic or cholinergic fibers to other target organs in our actual lower part of our abdomen and pelvis particularly the lower parts of the git and again works to be able to increase motility and defecation right and then for the actual general urinary tract it works on the bladder the detruster muscle to be able to cause an increase in motility of the detrusor muscle to be able to empty urine so these are important when you think about this with respect to these types of functions of the parasympathetic nervous system now the other thing that's really interesting is that we have another type of cholinergic pathway but it's not a part of the parasympathetic nervous system it's actually part of the sympathetic nervous system so i kind of want to give you a different color here so in the sympathetic part which is like t1 to about l2 we have sympathetic fibers and what these sympathetic fibers do is these actually go and supply so there's acetylcholine that's actually released in your preganglionic fibers we already know that you guys want some recap on that go watch our cholinergic videos and our autonomic nervous system videos but we know in all the pre-ganglionic synapses acetylcholine is released in all of these postganglionic synapses acetylcholine is released for this part of the parasympathetic nervous system for the cranial sacral outflow but there's one other area in the sympathetic part of the spinal cord generally from about t1 to about l2 this is where the sympathetic outflow is and the preganglionic fibers release acetylcholine and generally the postganglionics release norepinephrine for sympathetic in this case we don't and this actually goes to the skin this is one of the few examples where the postganglionic and preganglionic fibers of the sympathetic nervous system release acetylcholine and act on the skin and this will actually induce something called sweating so what i want you to remember is that the cholinergic pathway with respect to this part here can cause pupillary constriction change in the actual visual kind of like a near or far vision lacrimation salivation cause lower heart rate or bradycardia can cause bronchoconstriction can cause an increase in gi secretions and motility and inducing defecation and cause increased motility or contraction of the bladder causing urination and sweating these are important concepts now but there's one more thing that we have to talk about and it's a big one because this is a part of like our autonomic nervous system there's also something for the somatic nervous system you know what else is really interesting there's also cholinergic pathways that act with particularly within the cerebrum and within the cerebrum we're not going to go crazy down this rabbit hole but within the cerebrum there is also cholinergic pathways that play a role in cognitive function and so as we have patients who potentially get older or suffer from very specific diseases they may have a decrease in this acetylcholine pathways within their central nervous system and potentially develop something called alzheimer's or decreasing memory and so it's important to remember that these are a lot of the functions that this has to do with now here's what's really cool when we talk about the cholinergic system the drugs that we're going to be giving people they're particularly working at these target sites and you know what's really interesting is we'll zoom in on this but imagine here we're going to release acetylcholine and acetylcholine is going to have to work on this pupil or on the ciliaris muscle how the heck does it do that it has to have a particular receptor and that's what we'll talk about next because what happens is certain drugs that we give can act on the receptor and potentially act like acetylcholine stimulating the receptor causing all of the same mimicking type of effects or we can have another drug that can actually work to increase acetylcholine levels not by directly stimulating the receptor they can just increase acetylcholine levels by preventing a particular enzyme from breaking it down called acetylcholinesterase and we'll talk about that before we do that let's talk about the last function of the actual cholinergic system all right so the next component here that we have to talk about is that the cholinergic pathway is also involved with what's called our somatic nervous system so we talked a lot about our autonomic nervous system some of the actual central nervous system pathways in the cerebrum but we also have acetylcholine particularly released from these somatic motor neurons and what happens is this acetylcholine that we actually release can act on skeletal muscles so a lot of things that we were talking about up here with acetylcholine and working on our target organs up here was about smooth muscle cardiac muscle glands thus being a part of the autonomic nervous system or other types of neurons in the central nervous system for here we're having it work on skeletal muscles and what you guys need to know is that this helps to be able to produce skeletal muscle contraction so what this will do is cause contraction of these skeletal muscles so this is an important concept and we'll actually go into a little bit more detail about how acetylcholine particularly works on these target organs because what you need to understand is there's different types of receptors in order for acetylcholine to exert its effect we know based upon the concept of pharmacodynamics that a drug will potentially need some type of receptor to be able to bind to to produce its type of cellular response well in this situation here for these skeletal muscles it's what's called nicotinic receptors these are ligand-gated ion channels for all of these up here they're likely all going to be what's called muscarinic receptors and these are called g-protein coupled receptors when it's acting on the target organs so generally nicotinic receptors are located in two particular places one is on the skeletal muscle at what's called the neuromuscular junction neuromuscular junction here and the other one is that right here at these pre-ganglionic sites so the point where between you have your pre-ganglionic neuron and your postganglionic neuron we also have neuro what's called nicotinic receptors but generally at all these target organ sites they're going to be muscarinic receptors all right so now let's go ahead and take a look at this types of receptor pathways and going over how particular drugs are targeting specific receptors or specific enzymes involved in the actual acetylcholine in its response at the receptor site alright guys so now we need to do is take a look here let's actually zoom in imagine that we have here a target organ if you will okay so let's say that this is actually that somatic nervous system connection right so you have the somatic neuron releasing acetylcholine on the actual skeletal muscle cell so this is going to be our skeletal muscle cell this is going to be our muscle and particularly the skeletal muscle what i want you guys to understand is how does this actual acetylcholine process work because what we need to understand is whenever we have acetylcholine particularly being released all of this acetylcholine pathway acting on the receptor producing its response where do drugs come into play to work in this concept and then we'll do the same thing where we say okay let's take a look at muscarinic receptors the ones that are inhibitory the ones that are stimulatory have a good understanding of that and how do drugs actually come into play within that system all right so first thing whenever we have acetylcholine how do we actually make it well you know there's a molecule called choline that we actually get from our diet so choline is something that we get from our diet and we have special transporters that will bring the choline into the actual synaptic neurons then you know we have mitochondria right generally the mitochondria are important because they actually have these very special molecules here called acetyl coa and what we'll do is we'll take acetyl coa and we'll combine it with the actual choline and when we do we use this special like little pink cute enzyme here called choline transferase like a it's a choline acetyl transferase and what it'll do is it'll take all of these things combine them together so we're gonna have choline combined with the acetyl-coa and what we're gonna do is we're gonna make acetylcholine and we're gonna put this into these beautiful little vesicles here so now out from this enzyme we're going to make acetylcholine and put them into these vesicles now what happens is once there's some particular stimulus let's say for whatever reason this neuron becomes activated an action potential moves down the somatic neuron when action potentials move down the somatic neuron what do you guys know about that you guys know that it actually opens up what types of channels on the synaptic neuron you guys know this come on this would be our voltage-gated calcium channels and what happens is calcium will rush into this particular synaptic neuron and what it'll do it'll actually help to be able to stimulate the fusion of the seed the actual vesicles containing acetylcholine with the actual membrane of the synaptic terminal and then via what's called exocytosis will release our acetylcholine molecule out into the synapse now once it's out there acetylcholine sees we're going to draw it like here's like this little dot here so it's going to be this is acetylcholine acetylcholine will come and bind onto these little like pockets on these little receptors what are these receptors here called i know you guys know it this is called a nicotinic receptor and what i want you guys to remember if you guys remember from the pharmacodynamics lecture that nicotinic receptors are what's called a ligand-gated ion channel so they're a protein channel they have a little pocket where acetylcholine will bind now normally these channels are kind of closed because there's no ligand bound to it and so imagine that there's like a little gate here blocking this off so imagine it's like this but once the acetylcholine binds with the actual a little pocket there it opens up the gate for all of these and now this gates open which it used to be prior closed what's going to start moving in sodium ions will start rushing into the actual muscle cell as sodium ions rush into the muscle cell it starts making the inside of the muscle cell positive depolarizing the actual muscle cell and what we know is that as we depolarize a muscle cell we'll activate that whole sarcoplasmic reticulum release calcium cause the whole cross braids we already know this but we'll induce a muscle contraction that's the whole process now after we've stimulated the muscle to contract what has to happen we need it to relax baby so how do we get that bad boy to relax get acetylcholine out of there so what happens is in order for acetylcholine to not be present we got this enzyme here you see this like dude with a honkin nose right there this enzyme here is called acetyl choline esterase one heck of a name but what this acetylcholinesterase will do is it'll actually break down the acetylcholine and when it breaks down the acetylcholine so here's the acetylcholine it'll get broken down by this particular enzyme into those constituents specifically choline like the acetyl groups so now it's rendered ineffective we can't utilize it anymore and so the acetylcholine levels within the synapse drop and then now the muscle will no longer contract that's an important concept because we can actually utilize drugs to potentially work at this actual nicotinic receptor maybe act like acetylcholine you know we have drugs potentially they can act like this and bind that little pocket open up these channels and have ions flood in induce contraction or we can have drugs particularly that work and then what would they what would you want to do think about this this guy works to be able to break down acetylcholine if i want to give drugs that act like acetylcholine what would i want to do i want to try to indirectly maybe increase my acetylcholine levels by inhibiting acetylcholine esterase if i inhibit acetylcholinesterase while i break down acetylcholine no what will happen to the acetylcholine levels in the synapse they'll increase and it'll act just like as though i'm stimulating that actual receptor okay the next concept here is we have this same thing that we're going to go over but we're going to go over this with muscarinic receptors this is the same concept so we should actually be very quick with this we take what choline we bring choline we're only going to do it from one side here into the actual synaptic terminal it combines with acetyl coa acetyl coa whenever it combines with the choline will get converted into acetyl choline via this enzyme the choline acetyl transferase put into the synaptic terminals an action potential moves down the axon when an action potential moves down the axon it does what to the actual terminal here activates these special channels here called voltage-gated calcium channels calcium channels open they flood into the actual synaptic terminal and stimulate diffusion which leads to what type of process the synaptic vesicles fusing with the actual cell membrane and releasing the actual acetylcholine via exocytosis now once the acetylcholine is released via exocytosis it can act on receptors in the same way it acts over here by the nicotinic receptors we can have it act on muscarinic receptors what i want you to know is this could potentially be a muscarinic receptor let's say i'm going to give you an example generally the muscarinic receptors that are inhibitory so we have particularly muscarinic receptors that are inhibitory so we're going to have inhibitory receptors if you will they're going to try to be able to slow things down inhibit things this means it would work through a very special type of g protein coupled pathway you know what that g protein coupled pathway is called this is called the g inhibitory pathway and the primary there's a lot of muscarinic receptors but the primary one that i want you to remember that inhibits is the m2 receptor in some degree m4 receptors but i don't want to make it too complicated m2 receptors is the one that i want you to remember now how does this happen acetylcholine here it is right we're going to have acetylcholine working on these two sites here so acetylcholine will come over here and bind on to this receptor when it binds onto this g-protein couple receptor it changes its shape when it changes its shape it activates a protein here called a g-protein and this is a g-inhibitory protein we know that that will release gdp and be stimulated by gtp so we know gtp will actually bind to this when gtp binds to this it then becomes active and moves along the cell membrane and works on an enzyme called adenylate cyclase but what would it do to a deny cyclist this is a g-inhibitory it'll inhibit adenylate cyclase he's normally supposed to take atp and convert it into cyclic amp which helps to be able to activate protein kinases but in this situation you know what protein kinase is supposed to do they're supposed to phosphorylate proteins to perform specific actions but what we're going to do here is we're inhibiting this enzyme it's not going to perform this function so it's not going to make atp into cyclic amp we're not going to get protein kinase a and therefore because of that we're going to get decrease in the phosphorylation of particular proteins so all this phosphorylation reactions that are supposed to work on particular proteins we're not going to get you know why this is a great example because in our actual heart muscle or particularly the actual nodal cells of our heart this is important because we have specific channels that we want to phosphorylate to be able to open up and allow for ions to flow in right like calcium or sodium and these are supposed to be phosphorylated in order to do that if we don't phosphorylate these they're not going to open up and allow for ions to be able to flood into them and we won't be able to stimulate this actual nodal cell the av node you know what else is really cool g inhibitory protein know what else it actually does there's three units of it three subunits there's an alpha a beta and a gamma what happens is this g inhibitory subunit the actual beta and gamma subunit can actually bind on to potassium channels now you're like what the heck potassium channels where did that come from when it binds onto these potassium channels that that g inhibitory like the beta gamma subunit it'll bind on to this like little part here so here's going to be the part of that g protein some part of it the beta gamma subunit when it binds onto it opens up these channels and allows for potassium ions to leave the cell if potassium ions leave the cell what happens to the inside of the cell it becomes negative if you make the inside of the cell negative what do you do to its actual activity you decrease it and now won't be able to generate action potentials this is a perfect example of what type of tissue over here where we wanted to slow things down the av node the heart to lower heart rate so this would be a great example of an av nodal cell so if i gave a particular drug that act like as a direct agonist on that muscarinic receptor what would be the overall response it would inhibit this particular cell from functioning or if i gave a drug that worked again that same concept the acetylcholinesterase i inhibited it caused an increase in acetylcholine the increase in acetylcholine will stimulate an increase in this particular pathway causing the inhibition of that cell it's the same kind of concept now the other types of cells that are actually going to have receptors that are stimulatory stimulatory receptors there's a bunch of these i don't want us to get lost down the rabbit hole what i want you to remember is that these are usually coupled to gq and some degrees g stimulatory proteins but i want you to primarily remember gq proteins and the primary one that i want you to remember is m3 receptors muscarinic type 3 receptors technically m1 m3 m5 but m3 is the most important one so m2 is the most important inhibitory one m3 is the most important stimulatory one it's the same concept acetylcholine binds on to this receptor changes its shape activates a g protein so it gets rid of a gtp binds a gtp when it becomes stimulated activates an enzyme this is called phospholipase c phospholipase will break down parts of the cell membrane a molecule called pip2 and break it down into something called dag which is called diaceal glycerol which activates protein kinase c and ip3 which works to be able to increase the calcium outflow from what's called our sarcoplasmic reticulum or from the endoplasmic reticulum and the whole concept is that if you have an increase in protein kinase in an increase in calcium you're going to be able to cause a lot of phosphorylation of particular types of proteins and increase the activity of these particular proteins increasing the response for example let's pretend that this is a smooth muscle cell this is a smooth muscle of the git acetylcholine gets released activates this m3 receptor increases the activity of the phospholipase c increases diaceal glycerol increases ip3 if you increase these they're going to activate protein kinase c increase calcium levels protein kinase was phosphorylated particularly channels to bring more positive ions into the cell if i bring more positive ions into the cell and i cause the inside of the cell to become very positive what am i going to do to the inside of the cell when i make it depolarize and then subsequently contract and that would increase the gi motility so you understand where the difference comes in between these all right so if i gave a direct agonist to act on this muscarinic receptor it produced the same exact response or if i gave a drug that inhibited this acetylcholinesterase it would increase acetylcholine indirectly and give the same type of response because again what happens to the acetylcholine it gets broken down by this molecule into what's called choline and then it's acetyl group product and gets recycled and that's via this acetylcholine and i'm just going to put esterase so that leads us to the next point what are the drugs that i can actually give to work as direct agonists on either a muscarinic receptor or a direct agonist on the nicotinic receptor and what are the drugs i can give to inhibit the acetylcholinesterases to increase the acetylcholine and still produce the same type of effect let's talk about that now all right so when we talk about these let's make sense of a direct agonist they're going to work either directly at the muscarinic receptor or directly at the nicotinic receptor so which are the ones that are actually going to be direct agonists so i want you to remember bethennical methacholine pylocarpine and carvacol now methanocol methacholine and pilocarpine it's actually nice thank goodness they all work on muscarinic receptors only so what i want you to remember for these is that it works only all of these let's actually do it like this so we can save ourselves some time and pain here is that all of these work on muscarinic receptors okay and the type of muscarinic receptor they work on depends upon the target organ or their indication that we'll talk about later for example methanocal may work very heavily on m3 receptors because it loves to cause an increase in gi motility and and detrusor activity methacholine loves to act on particularly types of m3 receptors and cause bronchoconstriction pilocarpine may act on some of the m3 receptors as well and carbicol what about this bad boy this one can actually work on both this is the only one that acts on the muscarinic dang thing i can't spell these damn things muscarinic and nicotinic receptors so it's actually relatively easy to remember your direct agonist right and which ones work on the muscarinic pretty much all of them except carbacol which acts on our nicotinic receptors and muscarinic receptors which is actually nice because we never really use carbocal anymore anyway but we gotta learn about it alright the next concept here is the indirect agonist so these are the ones that are working what way so again we talk about these you're particularly working to stimulate the muscarinic receptors these were those g protein coupled receptors you're trying to stimulate these bad boys for this one you're trying to work on the g protein coupled receptors stimulate them but you're also trying to stimulate the nicotinic receptors as well for this one over here they don't even work on the dang receptors they work on that cute little enzyme that acetylcholinesterase enzyme and because of this one what we need to be able to understand is that we know that all of these are going to work on the acetylcholinesterase but what's an important concept to understand is which ones will actually inhibit this particular enzyme to where it's reversible so it's reversible meaning if i inhibit this enzyme there is a possibility that it will stop inhibiting it that's an important concept okay because if we can't rever if we can't reversibly uninhibit that enzyme then we're going to have some serious problems and that's one of the dangerous things that the military system is actually utilized with this last one or the types of categories in this but whenever you have something that's reversible it also determines its kind of onset or length of action for example edraphone edraphonium is very short so very short acting doesn't last very long maybe like honestly up to a minute max physostigmine neostigmine those are also relatively kind of like shorter acting as well but one of the big things is like peridot stigma pyridostigmine this one is actually like relatively in comparison to all of these hydrophonium physostigmine neostic mean peristigmine it's probably one of the longer lasting ones the other thing that's also important to remember is that physostigmine donepezil and rivastigmine are all what's called tertiary amines so let me actually write that down so physo i'm going to put fiso and donepezil and rivastigmine are all what's called tertiary amines meaning they are very highly lipid soluble meaning that these can penetrate into the central nervous system increase blood brain barrier penetration and that's an important concept so these are particular drugs that maybe the nepazil river stigma another drug called glantamine are very good for penetrating into the central nervous system for maybe cognitive function types of things for example alzheimer's where they have a decrease in cognitive function due to a decrease in their acetylcholine pathway if we increase the acetylcholine within those actual central nervous system pathways we could actually improve some of their cognitive function and these would be good drugs pfizer stigma not necessarily that good at that but you get the point all right so reversible indirect agonist is going to be this particular group big things remember edraphonium very very short acting pyridostigmine is the longest acting in comparison to edraphonium physio stigma neostatic meaning and peristigmine and then physostigmine uh donepezil rivastigmin another drug called galantamine are highly lipid soluble because their tertiary means so they can cross the blood-brain barrier the last one is ecothio fate or any other kind of things that are similar to this so one of the scary things of a similarity so a similar so similar kind of like drug class so within this think about you know the drug called sarin which is the nerve gas or any kind of pesticide organophosphates they act like this drug this was a drug that we actually utilized in glaucoma but we don't utilize it anymore because of this severe side effect profile and we have better drugs so what the fearful thing about these types of drugs especially things like sarin or pesticides organophosphates and things like that is that these are irreversible so these are air reversible inhibitors of that cute acetylcholinesterase enzyme so you won't be able to uninhibit them and that's a very scary thing because what happens is what these drugs will do is they'll put something called an alkyl group on this enzyme so imagine that you put like this alkyl group here's the alkyl group and it kind of inhibits the enzyme it prevents it from being able to perform its function what happens is certain other enzymes may come in and remove that alkyl group that's a problem if you do that let's say that we actually go from this point where it has the alkyl group and then what you do is it's you remove a piece of it you remove a piece of the alkyl group that piece is actually if we have to reverse this drug for whatever reason because of toxicity if we remove a piece of that out group so not only has this this is a very dangerous situation we can never go back to this point here if a patient gets a drug like sarin or an organophosphate type of thing or a pesticide or eco thiophate and they start developing toxicity because of it so cholinergic crises types of effects if we give them the antidote the pralidoxime at this stage when they have the alkyl group on them they would actually be able to be reversed but what happens is these special types of like phosphorylating enzymes come in here and lay down some phosphates onto this and remove a piece of the actual alkyl group now this can't be reversed so you can give them paraldoxin but it will not work this is an important concept they may ask you on your exam and this is called aging i'm not even kidding it's literally called aging so if you give the actual antidote whenever the enzyme is in the aging state it will not be reversed and you'll continue with the cholinergic crisis meaning that you've removed a piece of the alkyl group and it has a phosphorylated group on it if you give the antidote in the point where the alkyl group is added there's no phosphorylation there's no actual piece that's actually removed off of the alkyl group then you can actually reverse the underlying toxicity that's an important concept all right my friends we talked about the basic kind of mechanism of action all these different drug categories now what we need to do is talk about what kind of conditions we utilize these drugs for individually and then we'll talk briefly about a cholinergic crisis as the adverse effect of these drugs all right so let's now talk about the indications the uses why do we actually give these particular drugs now there's not a ton of reasons other than what we'll talk about as mice and the gravis but there's a couple other ones that we could actually consider in certain conditions so you know when a patient has like very little gi motility very little kind of you know bladder contractility in situations especially like post postoperative so generally whenever they have patients have decreased motility of the git and actually the bladder postoperative we can actually give particular medications to increase the motility so we can increase the motility of both of these particular organ systems in situations such as a post-op ilias it also could be due to postpartum so you know postpartum whenever patients have postpartum urinary retention that could be one particular reason or diabetes mellitus and diabetes mellitus can actually cause gastroparesis or decreased types of nerve stimulation so you can also see this particularly as what's called gastroparesis so we may give these particular drugs and what are some of the drugs that we can give one of them that i would actually want you guys to remember is what's called the bethenny call right so bethanical would be one particular drug the other one that you could potentially consider here is um physostigmine but we don't usually give this one just because it has a lot of cns toxicity so peristigmi neostigmi maybe other doable options i would say neostigmine would be the preferred agent just because it's a shorter acting not as long acting and then the next one i would say is consider pareto stigmine all right so these would be the particular agents that we could give to potentially increase gi motility in situations of post-operative ilias postpartum urinary retention or some type of like neuropathy in situations like gastroparesis in patients who have diabetes all right the next other reason reason this is actually an interesting one so we can actually give that drug called methacholine and what methacholine does is it actually helps us in something called bronchial provocation tests so what is it for it's called bronchial provocation tess and all that means is i have a patient who i'm concerned potentially has maybe asthma or some type of copd or something like that but particularly asthma in patients who have asthma normally their bronchial smooth muscle is super hyper responsive so it doesn't take much to cause these actual smooth muscles to go into an intense contraction what does the actual drugs that are agonists of our parasympathetic in other words remember the vagus nerve cause bronchoconstriction what are we going to do we're going to increase the acetylcholine in those synapses on the smooth muscle and cause it to bronchoconstrict even more so if i give methacholine to a patient who has asthma what am i going to see i'm going to see an intense bronchospasm and when it causes this bronchospasm it'll cause their bronchospasm to drop their what's called forced expiratory volume okay so it'll cause a bronchospasm that will decrease their forced expiratory volume in one second greater than 20 and that's a test that we can utilize in a diagnostic aid in situations like asthma okay so these are two particular reasons now let's come down and talk about things like glaucoma and secretions particularly like from the eyes and from our actual oral secretions all right my friends the next situation here is what if we have a patient who has something called glaucoma so you know there's different types of glaucoma there's open angle there's narrow angle glaucoma but the problem is that we're having an issue being able to drain the aqueous humor into these like little channels here so you know you have like these tiny little channels i'll kind of just highlight it here in pink like it's called the canal of schlem and this little area that's where you're kind of draining some of the aqueous humor now in situations of patients who have glaucoma what we can do is we can actually help to change the pupil size and the ciliarious muscle so what i can do is to help improve the drainage through this canal of schlem is i can help to pull the ciliaris this way and if i pull the ciliaris this way it opens up this angle here and improves drainage into the canal slim which would help to decrease some of the pressure inside of this actual anterior chamber and posterior chamber the second thing i can do is i can take the pupil right so the pupil is where the fluid such as the aqueous humor moves from what's called the posterior chamber into the anterior chamber what if i did something right where i worked to be able to help improve this actual angle now here's another particular reason so you know here we have that canal schlem right what if i take this pupil and what i'm going to do is i'm actually going to constrict it so this may seem interesting right but when i have what's called that acetylcholine working on these m3 receptors on the pupil what will they do they'll cause pupillary constriction so they'll decrease the size of this pupil hole now this may seem odd like how is this going to help let me explain how what i can do is let's imagine here is my normal pupil and then right next to this is that drainage right so here's that drainage this is normal okay if i have a patient who has pupillary so let's say that this is actually going to be normal what i'm going to do is let me actually make this a little bit of a bigger pupil hole here if i have them undergo pupillary dilation you know what happens with people are dilation they're going to actually undergo a lot of dilation and this space here is going to increase and it's going to bunch up near this actual base so then it's going to look like this so it's going to look like this now so it's bunched up so we have a larger pupil here but look what we're going to be doing we're going to be kind of compressing here that actual canal schlem i'm going to be compressing it and that's going to be altering the actual drainage of that actual canal slim now what if i do if i actually take and i actually constrict this pupil so if i constrict this pupil i'm going to narrow out my base if i narrow out my base now look what that's going to do it's going to improve and open up that canal schlemm and allow for better drainage through that reducing the intraocular pressure so in patients who have glaucoma what i can do is is i can cause one the dilation of the pupil and that'll actually help to open up that canal of schlem or the second thing is i can actually cause ciliaris contraction and that will pull this backwards so it'll pull this whole structure backwards more and help to be able to open up that actual angle so these are great drugs that you can give in situations of patients who have what's called narrow angle glaucoma so that's one particular situation we could also give now what would be a drug that i could actually give here i could give a drug called pilocarpine so pilocarpine that would be one drug you can also give another drug called carbocal but we don't actually give this one anymore just because pilocarpine is superior and also carbicol has a lot of toxicity and side effects there's also some debate that actually physostigmine could also potentially could be used as well but i wouldn't go too crazy down that one but you can actually do a plus or minus as faso stigma according to the literature all right but i would primarily focus on pilocarpine now the other thing here that pilocarpine carbacol also are actually decent at is that they also not only can actually cause contraction of the uh contraction of the ciliaris pulling that angle opening it up that angle and allowing for a better venous drainage into the canal slim or dilating the pupil narrowing out their base last compression of the canal slim but they also can act on those glands so it can act on our lacrimal glands and increase lacrimation so we can give these drugs and they can act on those actual muscarinic type 3 receptors and increase lacrimation and increase salivation and now why in the world would you want to do this two reasons one is a patient has a disease that destroys these salivary glands and lacrimal glands you know what that disease is called it's called shogren syndrome so it's an actual autoimmune disease and we can give this particular drug to be able to help improve some of that actual salivation and lacrimation especially if they have what's called corrado conjunctivitis zika and so again this would be particular reasons we would do that this is an autoimmune disease right so it's an autoimmune attack of those glands the other one would be radiation induced so if someone had some type of radiation therapy and they actually caused some type of necrosis or fibrosis of some of the ducts and glandular tissue it may actually do reduce some of the secretion and drainage into the oral cavity or and onto the actual eye and so if we can actually help to improve some of that by giving these drugs such as pilocarpine carbocarpisostigmine i'm sorry pilocarpinocarbicol this will be able to improve salivation and lacrimation so the two drugs that i want you to remember for lacrimation salivation is going to be pilocarpine and carbicol all right my friends so that's going to be these types of indications there's a couple more we're almost done let's kind of move on now to the next big indication for these drugs and that's myasthenia gravis all right my friends so now what we got to talk about is actually the use of these drugs in myasthenia gravis so my state of gravis quick little recap on what that is it's a disease in which you have an autoimmune attack particularly where you make auto antibodies that are attacking the nicotinic receptors and they're blocking the nicotinic receptor ligand site so where acetylcholine is supposed to be able to bind and produce its type of muscle contraction effect it's being blocked by these nicotinic receptors and so the patients develop an inability to contract their muscle which will cause weakness right so that's the key feature is that they'll develop what's called weakness and obviously a very specific muscles we're not going to go down that route what you need to understand is that we can utilize particular drugs to improve weakness in these patients and so what we actually would do is we can give a couple different drugs one of the things i'm going to do is i want to talk about a couple different drugs and what they're going to do is they're all going to inhibit the acetylcholinesterase and what we know about this drug is that acetylcholinesterase will take and do what it's supposed to be able to take acetylcholine so here's our acetylcholine that's in the synapse here it's supposed to take and convert it into choline into a small like acetyl group and then be reutilized right but it renders acetylcholine inactive okay if i inhibit this enzyme i prevent this type of process and i decrease the actual breakdown of acetylcholine if i do that i start increasing increasing increasing increasing increasing acetylcholine in the synapse so much so that it actually starts competing with the antibodies and knocking these antibodies out of that actual site and if i start beating some of the antibodies out of that site then acetylcholine will potentially be able to bind to these actual receptors maybe some of them still will be bound to the actual nicotinic antibody but maybe some of the acetylcholine will be able to beat that receptor beat that antibody out of that actual receptor site and that's an important thing because then what we can do is we can have an improvement an ion influx into this portion here and maybe have some type of contraction that decreases the weakness right that's the whole goal now what kind of drugs could i actually do well they obviously have to be acetylcholinesterase none of these are going to be any direct type of like a nicotinic agonist okay they're not going to be good enough in these situations so we need to be able to increase the acetylcholine to high levels now there's a couple different drugs here the first one is not used to treat so again what is this disease here called let's actually write this down this is actually going to be used in what's called maya steenia gravis and it's again it's an autoimmune disease where antibodies attack the nicotinic receptors block acetylcholine preventing them from being able to contract they develop weakness if we give acetylcholinesterase inhibitors they'll increase the acetylcholine and beat the nicotinic receptor antibodies out of that site and still be able to bind and produce some type of stimulation to the muscle reducing the weakness the drugs i could give first one is called edraphonium now edrafonium is not going to be used to treat it is not used to treat myasthenia gravis it can be used to help diagnose myasthenia gravis and we call this test where we give edraphonium and help us to see if there is a possibility we call this what's called the tensile on test and it's actually a really cool test so edraphonium is a very short acting drug like honestly you might get about a minute or two out of this drug so if you have a question if a patient has myosinographs they're really weak let's say that they're not able to move their arms up very much they're very very weak in their arms you give them edraphonium edraphonium inhibits this particular enzyme increases the acetylcholine in the synapses for about a minute or two knock some of these actual antibodies out of the ligand site you stimulate those receptors you should see an improvement in their weakness and it's very short-lived and so that would be one of the things that we could utilize in helping us to aid in the diagnosis of myasthenia gravis obviously that's not the most important test obviously we have to check the antibodies but it helps us in the diagnosis that's one cool drug the next one that we should talk about here is we have the other drugs called physostigmine paretostigmine and neostigmine now with these neostigmine is really good in the treatment of myasthenia gravis but when we talk about time like like like it's not as long at lasting as compared to pareto stigma so when you compare the duration let's actually put duration of action duration of action in comparison between neo-stigmine and pyridostigmine it is significantly less than compared to parietal stigma protostigmine is a lot longer lasting so it's better in the chronic management of patients with myasthenia gravis so when we talk about these pareto stigmine i would want you guys to remember that pareto stigmine is a longer duration but either way i could pick between these neostigmine and pyritostigmine either one of them are utilized in the treatment of myasthenia gravis it's just more likely chronic long-term management would be better managed with pyridostigmine because i'm going to get about six hours out of that drug in comparison to neostigmine i might not get any more than about three hours out of that drug so it's an important concept to understand the last one that's actually a part of this group of the you know reversible inhibitors is the what's that one the physostigmine we don't utilize this drug and the reason why is we don't so stay away from no fiso and the reason why is because this one has cns toxicity so because it's very lipid soluble we do not want to give this one to treat myasthenia gravis because it will cause excessive excitation of the central nervous system leading to seizures convulsions and so that's an important concept to understand so that's why whenever we utilize these drugs adrophonium is used in aiding in the diagnosis via the testilon test tensile and the neo-stigma and parental stigma can be used in myosinic gravis but pareto stigma is probably going to be the preferred agent just because it has a longer duration of action and it's going to be better in the chronic management of myasthenia gravis okay i hope that made sense now one more really cool thing about edraphonium let's say that you have a patient who has myasthenia gravis and what we're trying to figure out is they come to the office and they say hey doc man i'm i'm getting more weak than usual i'm even more weak and i'm taking my medication i'm taking my pareto stigma i don't know what's going on so there they have myasthenia gravis and what you're trying to figure out is okay do they have what's called a myosthenic crisis meaning that their disease is getting worse in other words in myasthenia crisis they're having more antibody attack of their nicotinic receptors and you're giving them pyridostigmine right to try to be able to increase their acetylcholine but it's not enough their crisis is worse than the actual dosage of pareto stigma that you're giving them in other words they need more pareto stigma so you're giving them a drug to be able to inhibit the acetylcholinesterase to increase acetylcholine but they're just having such an intense attack autoimmune attack right now that they're having a big exacerbation that the dose of the actual pareto stigma is not enough to increase the acetylcholine to displace the receptors so they're having an exacerbation of their underlying myosinic gravis the other question that you have to say is is this a cholinergic crisis this is where it can be somewhat kind of confusing initially so a cholinergic crisis in other words am i giving them too much of the pareto stigma what does that mean maybe i have these acetylcholine binding onto these receptors very powerfully and i've given a dose of paretostigmine and it is really really inhibiting this particular enzyme where the acetylcholine levels are through the stinking roof and they are causing so much stimulation of this muscle that the excessive stimulation too much of one thing is always not you know not a good thing that too much excessive stimulation of the muscle will lead to weakness so in this situation the weakness that they were having was because they weren't getting any types of ions into this actual muscle cell and so that was because of their myasthenia they were having so much blockage of those receptors that they weren't getting any ions into their actual muscle cell and that was because of the disease getting worse and not a high enough dose of protostigmine in this situation you give them too much of the pareto stigma and increase their acetylcholine cause their muscles to be overstimulated and induce weakness you don't know which one it is what you could do is just say in this situation i would do what i would increase the dose of my pareto stigma send them home and see if they get better or i would decrease the per dose of the pareto stigma send them home see if they get better but that's a scary situation to do what if i had a drug that i could give that would only last about one to two minutes it would give me the answer and then i could send them home with somewhat of confidence knowing that i've given them the right answer to their situation that's where eduphonium comes into play if i give them edraphonium so imagine here let's actually say i give them edraphonium and the situation if i give them eduphonium what it's going to do is it's going to work to inhibit this enzyme even more if i inhibit this enzyme even more what am i going to do to my acetylcholine levels i'm going to increase my acetylcholine levels i'm going to knock some of these antibodies out of the site and then i'm going to allow for acetylcholine to bind to some of these actual sites and then that's going to increase ion influx and the ion influx that i'm going to allow for is going to cause more positive ions leading to contraction of the muscle and decrease the weakness so in a myosthenic crisis if i give them edraphonium it'll actually decrease their weakness it'll improve their weakness they'll get stronger and then i know okay that's the answer then they're in a mysterious crisis what's the answer increase parity stigmine send them home with that cholinergic crisis i give them edraphonium i'm going to inhibit this enzyme even more i'm going to increase my acetylcholine levels even more and then because of that i'm going to have more positive ions coming into the cell and i'm going to increase my weakness i would know right then and there if they have a worsening weakness or they have other cholinergic signs like you know diarrhea urination they have excessive salivation lacrimation they have bradycardia excessive kinds of cholinergic crisis types of findings i would be able to tell ooh do not increase the dose of their pareto stigma i would see an increase in their weakness with this and i would say this is likely a cholinergic crisis we have to hold some doses of protostigmine and then from the future we need to decrease the pareto stigmine doses i hope that makes sense the last thing that i want to talk about here with a couple other situations and we'll talk about the central nervous system drugs for cholinergic agonists is we can also utilize these drugs in somewhat of a way of overdoses so imagine a patient is taking an anticholinergic so they're taking a drug like an anticholinergic what are some anticholinergics well we're going to have that eventually in another video but a couple of them that are really important are things like tricyclic antidepressants atropine things of that nature and what these are potentially trying to do is that these are trying to decrease the acetylcholine levels and so what you can do is because these drugs are potentially acting at these you know nicotinic receptor sites or other types of sites what you can do is you can give them a very particular drug that would be able to get rid of or get the actual drug out of that potential site and reverse the actual toxicity of the tcas or atropine so if someone had an overdose of these particular drugs what could i give to be able to displace them out of these sites that the way they're not causing this anticholinergic toxic effect i could give them a particular drug called physostigmine so physostigmine would be a decent drug to be able to give in situations such as anticholinergic overdoses such as tcas or atropine or even like atypical antipsychotics the other situation is if i had what's called a neuromuscular blocker so if i have a drug called a neuromuscular blocking agent so i had someone who actually had to get paralyzed because they were getting intubated they were performing a surgical procedure and they needed to be held still in that situation the neuromuscular blocking agent is binding onto these nicotinic receptors and inhibiting these nicotinic receptors from being able to contract because we don't want the patient to move as we're cutting into them or doing some type of procedure afterwards when they're in the recovery unit and they're still not moving and you need to get them to move what we can do is we can reverse the effect of the neuromuscular blocking agent if we gave too much of it and we can give a drug that actually can competitively and this is what's really interesting it can competitively act here and knock that actual drug out of the site and that's where neostigming can actually come in so neostigmine is one of those interesting ones where neostigmine has the ability to act a little bit like a nicotinic agonist in a way and an acetylcholinesterase inhibitor so it can act as an indirect agonist and in some small degree even a direct agonist if you give this neostigmine it would be able to knock this neuromuscular blocking agent out of that site and then allow for the contraction of the muscle to reverse the actual paralytic effect so if you're trying to reverse a neuromuscular blocking agent you can give something called neostigmine and if you're trying to treat or give an antidote as an overdose to tricyclic antidepressants or atropine you can give fisostigmi all right the next thing we have to talk about is some of the things with alzheimer's disease all right my friends so the other thing i told you is that there's actually again cholinergic pathways within the central nervous system there's a really interesting nucleus it's called the nucleus of maynard and what this nucleus does it has like these cholinergic fibers that actually go up to the central like up to your cortex and provide cortical stimulation and this is important within our cognitive function right so our memory etc what happens is that in patients who have a disease called alzheimer's right and they start developing something like dementia or a decrease in their cognitive function what happens is because this pathway is releasing acetylcholine there's a reduction in the acetylcholine within these pathways and because there's a reduction in the acetylcholine this causes a reduction in cognitive function and what we can do is we can give particular drugs to work to actually increase the acetylcholine in the synapses to hopefully improve the actual cognitive function and improve quality of life in patients with alzheimer's and that's where we would give particular drugs such as we would give dinepizyl we would give something like rivastigmine and the other one that we didn't have written down over there but i'll actually mention it now called galantamine now the nice thing about these drugs is that they're tertiary means so they can penetrate into the actual central nervous system across the blood-brain barrier but these will work to be able to do what inhibit the acetylcholinesterase if they inhibit the acetylcholinesterase what will they do to the actual acetylcholine levels they'll work to increase your acetylcholine levels which will work to improve cognitive function and memory it does not stop the progression of alzheimer's it does not necessarily completely cure them of alzheimer's all it does is is it slows the progression of alzheimer's and hopefully helps to improve their quality of life so it just slows the progression of the disease it does not stop it it does not cure them in any way shape or form it's important to remember that the last thing that we have to talk about here there's lots of adverse effects of these drugs and some of them are not as severe as what we're going to talk about now but i think it's really important whenever you guys get an exam and they're asking you about a particular drug such as one of these and they start to have these particular types of effects are they in a cholinergic crisis or not and so this is actually really easy to understand you want to know why is because we have a strong understanding of our cholinergic system now and so if a patient has a cholinergic crisis it's going everything that we talked about on the complete opposite end of the board we're going to ramp it up they're pupils they'll have increasing meiosis their pupils will be like pinpoint they'll have increased lacrimation all right so they'll be kind of their eyeballs will be watering like crazy they'll be salivating they'll have just drool coming out of their mouth so massive salivation they'll have an intense drop in the heart because this acts on the m2 receptors and then subsequently a drop in there cardiac output that may cause hypotension drop in their blood pressure they may also have intense bronchospasm where they have difficulty being able to breathe and wheezing they may also have increased gi motility and so because they're just having tons of geomotility they're just shooting you know the chocolate rain is flooding from their hershey highway so they're having increased defecation and diarrhea they're causing contraction of their bladder and just shooting urine out like it's going out of style so there'll be increased urination and then on top of that they're gonna have excessive stimulation of our skeletal muscles and if you excessively stimulate the skeletal muscles too much what will actually this do this will cause weakness right so this may lead to weakness and then on top of that like i told you because some of these drugs can actually cause excessive stimulation of the central nervous system if you excite it too much it can cause agitation it can cause restlessness it can cause terms but what's the most concerning thing it can cause convulsions increasing the activity of the actual neurons can potentially do convulsions so if i give one of these types of agonists one of these cholinergic agonists and i maybe just give a little bit too much of that these are all of the effects that i could see but there's one more remember i talked about the sympathetic nervous system that was actually from the thoracolumbar output but the cholinergic system was a part of that remember the preganglionic release acetylcholine the postganglionic or that sympathetic neuron released acetylcholine act on the m3 receptors on these sweat glands and caused increased sweating so these are the big things to think about you know what actually a general a very intelligent person came up with a mnemonic to be able to remember these and the mnemonic is the mnemonic to remember this is dumbbells so you can kind of just look at it but diarrhea so excessive diarrhea excessive urination uh in this case they would actually have an intense pupillary constriction like meiosis they would also have bradycardia they would have bronchospasm they would also have excessive excitation of their muscles and central nervous system which can cause weakness and convulsions they can also have lacrimation they can have salivation and sweating so this is one of the potential ways to be able to remember this type of cholinergic crisis now the question that also may come up is what kind of drug can i give to reverse the actual cholinergic effects in this situation i want to give an anticholinergic agent and so there's two particular drugs i can utilize to reverse or give as an antidote one is atropine and the other one that i can actually give is called pralidoxine okay pralidoxine but again don't forget this guys remember i told you that you can give pralidoxine to a patient who takes an irreversible indirect agonist like the you know one of those nerve agents or pesticide agents organophosphates or the eco thiophile of fate we can give it but we have to give before what occurs aging where the alkyl group piece of it gets removed off all right we've talked a ton about cholinergic agonists i hope it made sense and i hope that you guys enjoyed it we're not done though let's do a quick couple of questions and see if you guys understand all this stuff all right ninjas let's do some questions here let's put our minds to the test let's see if you guys understand the cholinergic agonist so question number one botulinum toxin blocks the release of acetylcholine from the cholinergic nerve terminals what is a possible effect of botox so think about what acetylcholine does at the actual nerve terminals on a muscle so acetylcholine is supposed to be able to trigger the muscle to be able to contract all right so if there is an absence of acetylcholine because you're blocking its ability to be released what do you think is going to be the overall effect are you going to be able to cause skeletal muscle contraction no so there's going to be an absence of skeletal muscle contraction what's the opposite of a contraction paralysis so this should lead to skeletal muscle paralysis and that's one of the effects of the botulinum toxin so it should be skeletal muscle paralysis in this situation all right beautiful next situation here is we have a patient who develops urinary retention after an abdominal surgery so they're like a postop urinary retention an obstruction was completely ruled out as a cause for their retention which strategy would be helpful in promoting urination we have to remember again there's different types of receptors in this case the bladder is what's called a smooth muscle as we think about smooth muscle we know that there is specific types of receptors so there's nicotinic receptors and muscarinic receptors nicotinic are present on the pregang on the cell bodies or dendrites of the postganglionic motor neurons and they're also present on the smooth muscle cardiac muscle and glands of target organs for i'm sorry the i apologize the nicotinic receptors are present only on the uh the dendrites and cell bodies of the postganglionic motor neurons and on skeletal muscles apologize for that muscarinic receptors are found only on smooth muscle cardiac muscle and glands of target organs let me say that one more time nicotinic receptors are found on the dendrites and cell bodies of the postganglionic motor neurons and on the skeletal muscles muscarinic are present on smooth muscle cardiac muscle and glands now when we talk about that we know that the bladder is a smooth muscle now the question is which type of muscarinic receptor is it remember i told you that there's a bunch of different types but there was two main ones that i want you to remember m2 was the inhibitory receptor and you could also if you wanted to remember m4 m3 was the primary stimulatory receptor if you really wanted to remember m1 m3 m5 would also be stimulatory but if that's the case then we have m3 receptors here present on the smooth muscle of the bladder so that's going to want to promote contraction so if we have acetylcholine it'll bind onto the m3 receptor and produce contraction that's important so look at the question would we want to activate nicotinic receptors no because that's not present on smooth muscles it's only on the postganglionic motor neurons there were dendrites or cell bodies or skeletal muscle do we want to inhibit the release acetylcholine no i actually want acetylcholine to stimulate these m3 receptors do i want to inhibit the cholinesterase enzyme if i inhibit the cholinesterase enzyme that will increase the acetylcholine in the synapses and that'll actually have it stimulate the m3 receptor more that would be the correct answer and do i want to block the muscarinic receptors no i want to actually stimulate them so it has to be c inhibit the cholinesterase enzyme because that will help to prevent the breakdown of acetylcholine increase the acetylcholine in the synapse and have it stimulate the m3 receptors and cause smooth muscle contraction should be c all right three which of the following drugs could theoretically improve asthma symptoms we have to think about this all of the receptors on the smooth muscle of the bronchioles is going to be m3 receptors so whenever any kind of cholinergic agonist binds on to it it's going to cause bronchoconstriction to some degree methanocal that is one of those types of muscarinic agonists pilocarpine muscarinic again it's peristigmine it's a muscarinic it's actually going to increase the acetylcholine levels in the synapse to bind to muscarinic receptors and so these three are all going to cause bronchoconstriction atropine is the one that we did not mention and guess what atropine is an anticholinergic so it's going to oppose the normal muscarinic function so in other words all three of these are going to cause bronchoconstriction atropine is the exact opposite when it binds on to the muscarinic receptors it inhibits them and prevents bronchoconstriction thereby causing bronchodilation so the answer should be atropine if an ophthalmologist wants to dilate the peoples for an eye exam which drug class of drugs is theoretically useful in this situation well think about it what kind of muscarinic receptors are present on the the actual muscle of the pupils well remember this is going to be muscarinic 3 receptors and normally what does the parasympathetic do it causes pupillary constriction so if i stimulate the muscarinic receptors the m3 receptor of the pupil they're going to constrict so think about that then would i want to cause an agonist to bind onto that muscarinic receptor to cause it to dilate no because if i stimulate the muscarinic receptors agonist it's going to cause pupil constriction do i give an inhibitor an antagonist yes because if i block the muscarinic 3 receptors they will not constrict and therefore subsequently dilate just to continue though pilocarpine this is a agonist so it's an actual cholinergic again specifically a muscarinic neostigmine is a cholinesterase inhibitor so it's going to increase acetylcholine and that'll stimulate the muscarinic receptors so pilocarpine neostigmine and some muscular antigonus these are all kind of synonymous to one another so we want the antagonist to cause pupillary dilation in alzheimer's disease there is a deficiency of cholinergic neuronal function in the brain theoretically which strategy is useful in treating symptoms of alzheimer's okay think about it in alzheimer's there is decreased acetylcholine then all right there's decreased acetylcholine in the synapses if i give a drug that increases the acetylcholine in the synapses in the brain that would potentially be a beneficial situation so which one of those would give me that answer inhibiting the cholinergic receptors in the brain no that would make it even worse okay because if i inhibit the cholinergic receptors acetylcholine won't be able to even bind and produce its effect for cognitive function and memory inhibiting the release of acetylcholine that's again going to make it even worse because i have no acetylcholine in the synapses i'm trying to increase acetylcholine and its effect inhibiting the acetylcholinesterase enzyme in the brain oh that'd actually be a good idea because if i inhibit esterase i prevent the breakdown of acetylcholine and therefore i maintain acetylcholine levels in the synapse to stimulate this actual neuron and therefore improve the cognitive function in memory in patients with alzheimer's so it has to be c but let's keep going activating the acetylcholine esterase enzyme no that would be worse because again i'd be breaking down acetylcholine decreasing acetylcholine in the synapses so b and d are pretty much saying the same thing and then a is saying well if we have acetylcholine even if it's present it's not going to work at the receptor that's again the same concept overall it's producing less effect of acetylcholine or having less acetylcholine in the synapse so we want lots of acetylcholine in the synapse so it has to be c all right cholinergic crisis an elderly female who lives in a farmhouse was brought to the emergency department in a serious condition after ingesting a liquid from an unlabeled bottle found near her bed apparently in a suicide attempt she presented with diarrhea urination convulsions breathing difficulties constricted pupils and excessive salivation so remember the mnemonic that we talked about was dumbbells so diarrhea urination they're going to have also meiosis so they'll have the pupillary constriction okay then they'll have bronchospasm so breathing difficulties they'll have excessive excitation of their cns and their skeletal muscles so convulsions and potential weakness and then they'll have lacrimation and they'll also have salivation and then again in this situation here you can obviously see that they're going to have lots of salivation and they would also have lacrimation as well and sweating if they had sweating in here they don't mention that but either way this is a cholinergic crisis see most of the symptoms that's present there is definitely a cholinergic crisis so okay which of the volume is correct regarding this patient they consumed an organophosphate pesticide remember i told you organophosphates are those ones that cause irreversible inhibition of the acetylcholine esterase enzyme if you irreversibly inhibit the acetylcholinesterase enzyme you make the acetylcholine levels within the synapses stay elevated for a long period of time and if you don't catch it before they go into what's called aging it's not reversible you can't give them an antidote so it is likely that this patient does have organophosphate poisoning and that is likely the cause that it was some type of cholinergic agonist like an organophosphate an irreversible acetylcholinesterase inhibitor that caused this the symptoms are consistent with sympathetic no sympathetic would not produce these types of effects again sympathetic would not produce these parasympathetic effects her symptoms can be treating using using an acetylcholine anticholinesterase agent oh my gosh you kill them so if you give them an anticholinesterase you're going to increase their acetylcholine levels in the synapse even more so you'll worsen all this stuff her symptoms can be treated with a cholinergic agonist okay you want to put her into the ground a little bit quicker sure give her that but that's not going to benefit her it's going to again worsen her actual cholinergic crisis so it can't be c can't be d because you will absolutely murder them and b just is not going to be the effect sympathetic doesn't cause any of these types of effects so it's likely a all right a patient has received a neuromuscular blocking agent for skeletal muscle relaxation during their surgical procedures is experiencing some mild skeletal paralysis muscle paralysis after surgery which one of these drugs can reverse the effect of the neuromuscular blocker remember there's one that was an antidote or reversal of tcas tricyclic antidepressants atropine and antipsychotics and that was fisa stigma the one that reverses the neuromuscular blockers because it has somewhat of effect on the nicotinic receptors it can push the neuromuscular blocker out of that site and bind onto it would be neostigmine all right great 60 year old female has a cancerous growth in the neck region underwent radiation therapy her salivary secretions have been reduced due to the radiation she suffers from xerosomia dry mouth which drug is most useful in treating xerostomia we don't use acetylcholine anymore and atropine is an anticholinergic agent so we're talking about cholinergic agents anticholinergic means that you're going against parasympathetic remember parasympathetic you want to cause salivation lacrimation and those types of effects so atropine would oppose that so it can't be this one acetylcholine would be a good answer but we just don't use this drug ever and it comes down to pilocarpine and ecothiophate do you remember what ecothiophate was ecothiophate is actually going to be one of those irreversible anticholinesterases we do not want to use this it's going to have some nasty side effects and so we try to never use this drug and therefore the last one that would be remaining is pilocarpine so pilocarpine would be a potential drug and then the other one is carbocal but we don't use that one because it also has lots of side effects that would treat things like this situation glaucoma and also helping to be able to improve lacrimation and salivation in patients who have shogren syndrome or radiation induced decreased salivary and lacrimation so pilocarpine should be the answer 40 year old male presents to the family physician with drooping eyelids difficulty chewing and swallowing and just general muscle fatigue even on mild exertion which agent could be used to diagnose myasthenia gravis right then and there in this patient so obviously we send off acetylcholinestery the acetylcholine the nicotinic receptor antibodies so that's obviously the diagnostic test but we can give them a very specific drug that's very short acting lasts like maybe one to two minutes and what it's going to do is it's going to inhibit the acetylcholinesterase enzyme and increase the acetylcholines transiently for a couple minutes in the synapses to stimulate the skeletal muscles and give them more contraction and improve strength for that small time period what was that drug that i told you that we utilize as kind of a little diagnostic measure called the tensile test it's edraphonium edrophonium was the answer for that one good all right last question here is atropine um it comes from this plant called atrapabladana and it's a muscarinic antagonist right so it's an anticholinergic which of the following drugs or classes of drugs will be most useful in treat treating poisonings due to atropine remember i told you that neuromuscular blockers are going to be pushed out by neostigmine which drug pushes out tricyclic antidepressants pushes out atropine pushes out antipsychotics physostigmine so should be physocygmy all right engineers so that covers all the questions and that covers this video on our cholinergic agonist i really hope it made sense i hope that you guys did enjoy it and learned a lot love you thank you and as always until next time [Music] you