DIP Episode 20 - Autonomic Pharmacology Part 2

Welcome. My name is Divine. I am a fourth-tier medical student. This is the 20th episode of the Divine Intervention Podcasts. Today we're going to continue with Autonomic Pharmacology. So let's get right into it. Okay, so one thing I forgot to mention at the last podcast where I talked about Alpha 1 agent was one high-yield use of Prasusin. So Prasusin is an Alpha 1 blocker. It can actually be used to treat the flashbacks that company PTSD post-traumatic stress disorder. Remember your DSM5, you need one month to make that diagnosis. If it's less than a month, that's a good stress disorder. Okay, so let's jump to the Alpha 2 receptors. The Alpha 2 receptors, the NGI coupled receptors. Okay, so the inhibitor receptors, so the inhibitor denulates cyclase. So you ultimately get less activation of protein kinase A. And these receptors, it so happens that they are found on the pricinaptic adrenergic receptor. So it's sort of a negative feedback system for the sympathetic nervous system. So let's talk about agonists. Okay, so the goal of an agonist will be to help you release less neuropenechrine. Again, because it's a GI coupled receptor. So the big drug I'll talk about here is clonidine. Okay, clonidine is an Alpha 2 agonist. It's used to treat hypertension. It actually works extremely well. The only problem is once you stop the drug, you get rebound hypertension. And it's actually made a name nationally as a straight drug because it makes opioid withdrawal symptoms feel better.

Right, because if you really think about this opioids, the mechanism of action is the decrease the release of caracolovines like neuropenechrine at the adrenergic synapse. Right, so clonidine being an Alpha 2 agonist also decreases the release of caracolovines at the adrenergic synapse. So that it basically works as an opioid. It just uses a slightly different mechanism. Okay, so it will sort of temper the hyperadrenergic symptoms that accompany opioid withdrawal. Now, the next Alpha 2 agonist I'll talk about is alpha methyl dopac. Okay, the big thing you want to know about this is it's an anti-hypertensive that is safe in pregnancy. Okay, it's kind of big. So it doesn't cross the blood plus and toe barrier very well. Now, with regards to the Alpha 2 antagonist, right, so if you're inhibiting and inhibitor, right, that will ultimately make you release more neuropenechrine at the adrenergic synapse. Right, so we know one of these diseases, according to the mononaming theory, that's associated with a decrease in neuropenechrine. That's depression. Right, so if you increase neuropenechrine, you could potentially release symptoms. So that's the mechanism of action of a drug like metasapine. Metasapine is an anti-depressant that works as an Alpha 2 agonist and antagonist, rather. Okay, it increases the release of neuropenechrine at synapses, so it makes depression symptoms better. One big side effect you want to know is obesity with this drug.

Okay, it's process up a person's appetite. So it's probably a good choice on an exam in an anorexic patient that has depression. Or if they give you a question about an old lady that is not eating, that is sort of depressed, you can also give them retasapine. That'll be a nice agent for that. So now we're done with the Alpha receptors. Let's jump to the beta receptors. Okay, so start with the beta one receptors. Remember these are found in the heart. Okay, the positive I, it's a receptor where if it's activated, you can increase heart rate, right, so positive chronotropy. You could also increase contractility. That's a positive I notropy. Okay, and in the juxtaglomerulus cells that comprise the aphrine at the end of the brain, if you activate beta one receptors at that spot, you increase the release of rene. Okay, so the first thing I want to establish here is that beta blockers, right, so beta blockers that start with the letters A through M, okay, M is in Mandy, okay, they're all beta one selective, but beta blockers that start from the letter N like Nancy through Z, they're beta one and two. Okay, so they're nonselective. In general, you want to avoid the nonselective beta blockers in Asmatics, because remember if you block beta two receptors, you'll cause bronchoconstriction, and that can trigger airway compromise.

So the beta one selective blockers, right, so we have drugs like a tenon law, okay, Esmolal, uh, pro, uh, propranolol is nonselective, okay, um, and one other thing I will say with these beta blockers, uh, there's three beta blockers that have been shown to improve survival in heart failure, or improve survival, uh, uh, in like an ischemic cardiomyopathy, after a person has a myocardial infarction, okay, the easy way to remember them is just remember biochemistry, like the B, the C, and the M in biochemistry, okay, so the drugs here are B-sopro law, okay, they is carvidi law, it's an alpha-beta blocker, and then there is metopro, which is, uh, it's also a beta one selective agent, okay, so these drugs, the improved survival, they actually slow down remodeling of the heart, because no repinephrine, uh, you can actually induce a cardiac remodeling that can make a person's heart failure worse. But one thing you want to remember is yes, these drugs are good for heart failure, but you don't want to give a beta blocker in the setting of an acute heart failure exacerbation, right, because you don't want to cardio depress these people even more, uh, you also probably want to avoid a non-dihydroperidine calcium channel blocker under this scenario.

Okay, now some of those words with a beta blockers, right, so carvidi law, a beta law, the alpha-beta blockers, one special thing you want to know about a beta law is that it is in fact safe in pregnancy, okay, remember that numonic for the drugs that are safe in pregnancy, the anti-hypertensives that are safe in pregnancy, the numonic here is a hypertensive mom's love my fedipine, okay, so the hextance for hydrolyzine, the M stands for alpha method Dupa, okay, the L stands for labidolol and the N stands for my fedipine, okay, so labidolol is safe in pregnancy, another good thing about labidolol is that it's a great drug that can be given in a hypertensive emergency, okay, um, there are some other drugs you could also give drugs like nitroperside, be careful with your cyanide toxicity with that, and you can also give like my fedipine or my carvidi-pine, okay, and carvidi law, a beta law, there are also nice drugs that you can give in the setting of a cocaine overdose, okay, because you don't want to have the unopposed alpha-one viso-constrictive effect that can cause hypertension, so you can give labidololol on that dose circumstances, although the first line drug for the treatment of a cocaine overdose or a cocaine intoxication, if a person is severely hypertensive, is a benzodiazepine, right, so like lorazapam or diazapam or anything like that.

Now, another special set of beta blockers, we have aceptidolol and pindolol, okay, these drugs are partial beta agonists, okay, so yes, they're agonist, but they have partial activity, so they in fact present with beta-blocking actions, okay, because if you think about it, if you have more epinephrine around, you will get the full effect from activity in that receptor, okay, so drugs like aceptidolol and pindolol, by taking over those receptors, they are giving you less than a full effect, so they're basically exerting an antagonist effect if you may, okay, so again, think of those drugs as partial beta agonist for their classiclyr is described as being beta blockers.

Now, another special beta blocker here is an abyvolol, okay, one special thing about an abyvolol is it actually increases the release of nitric oxide in endothelial cells, okay, and remember nitric oxide is a potent viso dilator, okay, so it can actually lower your total peripheral resistance, so an unusual step one question will be a patient that should avoid, they could give you like some extra drugs and say, oh, which is the, which of the phonon is contraindicated with an abyvololol administration, right, you want to again avoid other drugs that can severely lower your total peripheral resistance, like cell denafilm, remember it's a PD5 inhibitor that's used to treat pulmonary hypertension, and it's also used to treat the erectile dysfunction, and you also probably want to avoid this in a person that's taking a nitrate, okay, now beta blockers, they do act as class two anti-rhythmics, right, so you can use them in a fib, okay, remember a fib classically is shows up on exempts as an arrhythmia that has an irregularly irregular interval, okay, you can also use beta blockers for an SVT, right, so super ventricular tachycardia, remember again the classic description of this kind of arrhythmia is a narrow complex regular tachyorythmia, okay, so it's originating above the AV node, right, so you have very narrow QRS complexes with that, you can also use beta blockers in heart failure, okay, so they do decrease myocardial oxygen demand because they somewhat cardio depress the heart, okay, and by slowing down the heart, right, they increase the astolic feeling time, so your end astolic volume actually increases, so you could potentially take advantage of the frankstalin relationship, and it also again, because the anti-rhythmics, they decrease the risk of dangerous arrhythmias that could cause death, okay, alternatively you could also use beta blockers in the setting of a t

hyroid storm, okay, usually you resort to non-selective beta blockers like proprylonal law, okay, the first thing proprylonal law does is it dumps down the hypogeonurgic state that accompanies a thyroid storm, but in addition it inhibits an enzyme known as a 5 prime diodinase, the 5 prime diodinase converts t4 to t3, okay, so by inhibiting that 5 prime diodinase, you decrease the formation of t3, okay, which again can dump down the responses of your body in the setting of a thyroid storm.

Other things you can use in a thyroid storm besides proprylonal law, right, you also want to use PTU, right, so PTU purple thylaryrocell, it inhibits thyroid peroxidase, okay, which is the red limiting enzyme of thyroid hormone synthesis, but it also inhibits the 5 prime diodinase that converts t4 to t3, okay, PTU one quick thing I'll just slide in here is that it's actually one of, it's actually the preferred anti thyroid medication in the first trimester of pregnancy, okay, but once you get to the second or third trimester, you want to switch to methemazone, because PTU has some nastier hepatotoxicity that you don't want to avoid, okay, so in a thyroid storm, you can also give steroids, okay, so steroids also inhibit the magic 5 prime diodinase that converts t4 to t3, but in addition to that steroids can also spurs up your adrenal axis, right, because there's been some reports that show that people that in thyroid storm actually have some kind of thyroid, some kind of adrenal suppression.

Another useful bit of blockers, you can actually use them in the setting of a sovajilvary sees, okay, use them for prophylactic treatment in a sovajilvary sees, you don't necessarily use them on the acute circumstances, if a person is having an acute virus, they will believe the first line drug you give is oxyretide, okay, no one really knows how true thyroid works for this purpose, but studies have shown that it reduces splanchonic blood flow, okay, but if you want to prophylax in the long term, against the sovajilvary sees you want to go ahead and give a non-selective bit of blocker, like perpranolone. Other things you can use for the prophylactic treatment of a sovajilvary sees, right, so you can give spironolactone, okay, spironolactone is an aldosterone receptor antagonist, okay, it does reduce a portal pressures, and in general, there is an antibiotic you usually add on in patients that have a history of a sovajilvary sees, as prophylax is against something known as spontaneous bacterial periodonitis, which actually has a pretty high mortality rate. The classic antibiotics that administer there are fluoroquino lots, right, so you can give like norfloxicin or ofloxicin or superfloxicin, okay, they're good prophylaxes against spontaneous bacterial periodonitis. Now if a person overdoses on a bit of blocker, how do you rescue those people? You rescue them with glucagon, right, so what's the mechanism behind that?

The thing is, if a person takes a bit of blocker, right, so better one receptors, for example, a GS-copboard, right, so when you block them, you have low levels of cyclic AMP. So if a person has bit of blocker toxicity, what you try to do is you're like, okay, wait, a bit of blocker dumps down cyclic AMP, let me try to raise that person's cyclic AMP in a different fashion, okay, so you could potentially give an agent that has activating activity, if you may, GS-copboard receptor, right, that GS-copboard receptor will increase the activity of a denilite cyclase and increase the conversion of ATP to cyclic AMP, okay, so it so happens that glucagon, glucagon works through a GS-copboard receptor, so you can raise your cyclic AMP in a different receptor as compared with a bitter receptor that has already been blocked with a bit of blocker. Another useful thing you should also think about with glucagon is you can actually use it as a rescue agent in severe hypoglycemia. It raises a person's blood glucose really fast. Another thing you could also use glucagon formula, this is more for a third year, is if a person has something stuck in their esophagus, the administration of glucagon can actually cause, it can cause more mass relaxation in their esophagus transiently and that can help that item pass, okay, and that's one of those bizarre things that we just pop up on an exam out of the blue.

And another high-yield thing with glucagon is a glucagonoma, right, so glucagonoma, right, has the same as the term says, right, it's a tumor that secrets glucagon, it's classically associated on exams with MEN1 syndrome, okay, remembering MEN1, you have parathyroid problems, you have pancreatic problems like a glucagonoma, and you also have pituitary problems, classically, a pituitary adenoma that secrets prolactin. So glucagonoma, the classic thing you want to know with that is these patients classically have diabetes, okay, because remember, glucagon's job is to raise your blood glucose levels and they also have a skin rash, right, so the classic, the skin rash is a classically termed on exams as an ecrolytic migratory erythema, okay, so again, remember the association on MEN1, so if you get an exam question about a person that has new onset diabetes and they have a skin rash, okay, and they potentially give you like hypercalcemia from a parathyroid problem, think about a glucagonoma with that, that's probably the first thing you want to jump to on an exam.

Now, let's go on to the beta-1 receptor agonists, okay, the big one I'll talk about here is Dubudamine, okay, you can give it in the setting of a CHF exacerbation, right, because in those cases the heart is not pumping very well, right, so by activating those beta-1 receptors, you provide some positive I-notropy to the heart, okay, you could potentially get that person over the hump of an acute CHF exacerbation, you could actually also use Dubudamine for cardiac stress test, okay, so if a patient cannot go on a treadmill, you can try to stress out the heart pharmacologically by giving a beta-1 agonist like Dubudamine, okay, now, a quick detour here, you can use Dubudamine for a pharmacologic stress test, but another thing you could actually take advantage of is a principle known as the coronary steel principle, okay, the coronary steel principle, and it also takes advantage of pharmacology, they use a different kind of pharmacology to stress out the heart or to induce a schemia if you may, so what's the coronary steel principle?

The coronary steel principle, when a person has a thrombus, right, so let's say they have a thrombus that's largely occluding one of the coronary vessels, the body tries to respond by maximally dilating that vessel, okay, now the thing is that vessel that's maximally dilated, it's great, right, it's helping you provide more profusion to that is schemic region of the heart, but that vessel that has been maximally dilated essentially loses its response to the administration of a viso-dialiter, okay, so that vessel maximally dilated, you give a viso-dialiter like sellostersol or diperidomol for example, that vessel would not have the ability to dilate any further, I mean if you sort of think about it geologically, you don't want that person's blood vessel to, that coronary vessel to pop, okay, so if that vessel is maximally dilated and you give a coronary viso-dialiter like diperidomol, it's a phosphodiester is inhibitor, I believe I talked about that in a previous podcast on hematologic pharmacology or sellostersol which is also a phosphodiester is inhibitor, okay, or regadenosine, regadenosine is a denocene analogue, remember adenosine is a very powerful coronary viso-dialiter, okay, so if you give these drugs, okay, you will dilate all the other normal coronary vessels, but you will not be able to dilate the stenosed vessel and when the other coronary vessels are dilated, you will increase blood flow through those vessels and if you sort of think about it this way, if you're increasing blood flow through those vessels, those vessels are effectively stealing blood away from the stenosed vessel because the resistance in those newly dilated vessels from the administration of the viso-dialiter causes more blood flow through them, okay, so because you're ultimately having less blood flow through the stenosed vessel, you begin to induce the schemic symptoms in the region of

the heart that is supplied by those stenosed vessels, that's the principle behind the coronary steel, or I guess the physiology behind the coronary steel principle, okay, this is probably a rare scenario but a weird thing they can give on an example, potentially, is to say, oh, what if a person has like three coronary vessels and all of them are stenosed and maximally dilated, you would not have a positive coronary steel test with those people, right, because all those vessels are all dilated, but that would be a super, super, super usual scenario.

As long as there is differential stenosis of coronary vessels, you would almost certainly have inducible schemia with the administration of the viso-dialiter when you're trying to apply the coronary steel principle. Now, next drug I'll jump to here is isoprotarinal. Isoprotarinal is a beta-1 and two agonist, okay, it decreases systemic vascular resistance, right, because by activating beta-2 receptors, you increase the synthesis of cyclic AMP, you cause smoke-moso relaxation, and you cause a viso-dialation, but it also increases cardiac output, okay, because it's a beta-1 activator, so one very nice thing they love to do on these USMLE exams is to try to test your knowledge of cardiovascular parameters like blood pressure and systolic blood pressure and the systolic blood pressure, and pulse pressure and all that fun stuff when you administer certain cardiovascular activities. I'll talk about that with me already in a few minutes, okay, so isoprotarinal in crisis cardiac output because it's a beta-1 agonist, but it also decreases your total peripheral resistance because it's a beta-2 agonist.

Now, for the beta-2 agents, remember again, your beta-2 receptors and GS couples with the increased clik AMP, so the cost with muscle relaxation, right, so you could potentially use your beta-2 agonists in the treatment of asthma, okay, so those are your terroles drugs, right, so like, how beta-rol, some matter-rol, for motor-rol, a beta-rol is a short-acting beta-2 agonist, okay, some matter-rol and for motor-rol, a long-acting beta-2 agonists, okay, you could also use these drugs to relax the smooth muscle in the uterus, right, so like the myometrium, you can use drugs like ridodrain, RITO, DRINE, or tributally, okay, these are both beta-2 agonists that can relax the myometrium in the uterus, okay, you could use them as tocoletics, right, so if you want to delay delivery, right, by stopping contractions for like 24 to 48 hours, you can use a beta-2 agonist like a ridodrain or tributally for that purpose. Now, one of the things you want to keep track of is that when you activate beta-2 receptors, around the silery body of the eye, you actually increase the synthesis of A.K.S. humor, right, so if a person has a disorder like glaucoma, where they have increased intracular pressures from too much A.K.S.

humor, you potentially want to give something that blocks those beta receptors, okay, so you want to give a beta-blocker like acybidolol or pindolol or needleol or timolol, okay, these are all beta-blockers that by blocking those beta-bidol receptors that you find around the silery body, you're doing in fact decrease the synthesis of A.K.S. humor. You could also treat glaucoma with an alpha-2 agonist, right, because again, let's reason through this physiologically. If you activate an alpha-2 receptor, you release less noripinephrine and by releasing less noripinephrine, you release less of an activator of the beta receptors on the silery body, so you ultimately make less A.K.S. humor. That's how drugs like aproclonidine and brymonidine work, okay, they're alpha-2 agonists that can be used to treat glaucoma. Now, let's take a small and talk about merino, okay, merino. So merino is a phosphodistory's inhibitor, it's classically used in IC Us, it's a phosphodistory's three inhibitor, okay, and remember that the job of phosphodistory is to break down cyclic AMP to AMP, okay, so you're basically an activator and cyclic AMP. So, if you inhibit that phosphodistory, if you inhibit that phosphodistory, you would have less breakdown of cyclic AMP, and like we said, cyclic AMP does different things depending on the kind of muscle we're concerned with.

So, if you're dealing with cardiac muscle, cyclic AMP leads to the activation of protein kinase A, okay, and when protein kinase A is activated, it phosphorelates phospholamban, okay, and when phospholamban is activated, I mean, when phospholamban is phosphorelithet, it becomes inactive, okay, so by inactivating phospholamban, you have less inhibition of a circle pump, okay, the circle pump is something that actively brings calcium into the circle plasma critical of cardiac muscle. So, phospholamban inhibits the circle pump, okay, so if you phosphorelate phospholamban with protein kinase A under the activity of cyclic AMP, phospholamban becomes inactive, okay, your circle pump becomes active, you put more calcium in the circle plasma critical lump, and as more calcium goes into the circle plasma critical lump, more calcium can also be released, which can ultimately A in the contraction of cardiac muscle, okay, so, myorelonation by inhibiting phospholdiesterase 3, both cyclic AMP levels in cardiac muscle, and causes cardiac muscle contraction, okay, but in smooth muscle, when you inhibit phospholdiesterase, you increase your levels of cyclic AMP, you actually have an inhibition of myocene-like chain kinase, okay, myocene-like chain kinase, and when myocene-like chain kinase is inactive, it, okay, you have less phosphorylation of your acting and myocene filaments, okay, and that causes smooth muscle relaxation.

So, the big takeaway here is high levels of cyclic AMP increase contraction of cardiac muscle, high levels of cyclic AMP cause relaxation of smooth muscle. So, let's talk about some cardiovascular parameters in the context of myorelon, okay, so myorelon, we know it increases cyclic AMP, right, so if you understood the spill, I just went on for the last like two minutes, you should be able to answer all these questions. So, what should cardiac output, what should happen to cardiac output if appreciated is placed on myorelon? It should increase, because again, your cardiac contractility is growing up. Now, what should happen to your end diastolic volume? What do you think? What should happen to your end diastolic volume? Well, I hope you're saying nothing, okay, because your end diastolic volume really has nothing to do with contractility, okay, so your end diastolic volume basically stays the same with myorelon administration. Now, what happens to your end diastolic volume? Well, it should decrease, right, because when you have better contractility of the heart, your stroke volume increases, right, and if your stroke volume increases, the volume of blood that's left in the heart at the end of systolic or contraction, which is your end diastolic volume should go down, okay, so if your heart contractility is increasing, what's happening to your stroke volume on myorelon?

It should go up, right, and if your stroke volume is increasing, what should happen to your systolic blood pressure on myorelon? It should increase as well, right, because remember, your cardiac output is a proxy for your systolic blood pressure. If your cardiac output increases, your systolic blood pressure increases, okay, your cardiac output is the primary determinant of your systolic blood pressure, okay, contrast that with systemic vascular resistance, that is determinant of your diastolic blood pressure, okay, so myorelon increases your cardiac output because it increases cardiac contractility, so it does in fact increase your systolic blood pressure, okay, now, what does myorelon do to the systemic vascular resistance, right, so think of, again, think of, what would mean here, your cyclic ampere levels go up in smooth muscle, smooth muscle constitutes your blood vessels, right, so you should have a decrease in your systemic vascular resistance, right, and if your systemic vascular resistance is going down, what should then happen to your diastolic blood pressure? It should go down as well, right, so we've already deduced that myorelon increases systolic blood pressure and decreases your diastolic blood pressure, so if myorelon is increasing your SBP and decreasing your DBP, what should happen to your pulse pressure?

It should become wider, it should increase, right, remember, pulse pressure is the difference between the systolic and the diastolic blood pressure, okay, so your pulse pressure widens or increases in the setting of myorelon administration, okay, and again, don't forget, again, myorelon by decreasing your SBR, you have to load is going down your Iotropy is going up again because it's improving cardiac contractility, okay, so let's keep going, so I will see where basically done with the sympathetic agent, so let's go ahead and jump to the parasympathetic agents, okay, the parasympathetic agents, so the first thing I will say is if you want to synthesize a cytocholine at a cholinergic synapse, okay, the first thing that happens is that sodium, right, remember sodium is primarily an extracellular ion, so as it goes down, it's gradient into a cell, you can use that gradient energy to pump things against their concentration gradient, so how is this relevant to our acetylcholine synthesis story? It's relevant here is that the first step in the synthesis of acetylcholine is that sodium as it goes down, it's gradient into a neuron, it can also drag cooling alongside, okay, so there's a sodium-choline sempoder that brings cooling into the cell, okay, there's a drug known as hemicolimium that inhibits that transporter.

The next thing that happens is that the cooling combines with acetylcholine, okay, under the action of cooling acetylcholine transferers or chat to make acetylcholine, okay, and then that acetylcholine is ultimately packaged into vesicol, okay, there's a transporter that actually makes that happen, that transporter can be inhibited by a drug known as the semicol, okay, the semicol vesicol inhibitor if you may, and then as an action potential travels down that neuron, right, you change the voltage of the neuron, okay, and as you change that voltage, a voltage-gated calcium channel opens, remember that's the channel that's blocked by auto-antibodies in the setting of lumbar-item-myostemic syndrome, okay, so calcium comes into the cell, okay, and that triggers the exocytosis of acetylcholine at the synapse from vesicles, okay, now the turn of mechanism for acetylcholine, right, is acetylcholine esterase, right, so acetylcholine esterase can break down acetylcholine into choline and acetylcholine, right, so you can repeat the cycle all over again.

Now, some high-yield pathological integrations here, first is botulism, okay, so remember the botulinum toxin cleaves the snare proteins, like your V and T snares that help you bring the vesicles to the membrane of the neuron to cause exocytosis and release of neurotransmitter, so the botulinum toxin, it's mechanism of action, is it cleaves those snare proteins, okay, and by doing that, you decrease the release of acetylcholine, okay, so how do people get botulism, right, so there are two ways you can get botulism, they love to test this on exams to see if you can differentiate between how a neonate gets botulism and how an adult gets botulism, so how does a neonate get botulism, they contract botulism, if for example, they take honey, okay, so that's why we did it, you say, oh, don't give your kids that are less than a year old honey, right, because honey can contain a botulinum spores, okay, and those spores, they can actually germinate in the GI tract of neonates, because neonates, they don't have a very robust GI flora, so those spores can germinate, okay, as those spores germinate, they release the botulinum toxin, and then that can cause a lot of trouble for the neonate like a flassey paralysis if you may, but an adult has a robust GI flora, okay, so in general, botulinum spores can not germinate in the GI tract of an adult, so how does an adult get botulism, we can get botulism if they consume the preformed toxin, not the spores, the preformed toxin, okay, and the classic exam scenario here is when an adult consumes humcand goods, okay, they can get botulism with that, okay, and again, remember, ultimately with botulism, you have decreased release of acetylcholine at the colineurgic synapse, so you get flassey paralysis, okay, another pathological integration here is myastinia gravis, okay, in myastinia gravis, you essentially form autoantibodies against the ni

cotinic acetylcholine receptor, okay, or I guess just think of primarily acetylcholine receptors, and when you make those autoantibodies, acetylcholine cannot bind anymore, okay, because again, you're making a competitive inhibitor of its receptor, and if you really think about that, they can actually test that very easily in the context of mechelisminthen kinetics, okay, so if a person has myastinia gravis, right, there are acetylcholine receptors, or pretty under competitive inhibition physiology, right, so under those circumstances your V max does not necessarily change, but your KM goes up, so that signals decreased affinity of acetylcholine for the acetylcholine receptor, and in myastinia gravis, right, the classic test, and I'll say right now, like clinically, the first line test in the diagnosis of myastinia gravis is to get anti acetylcholine receptor, anti-bodies, okay, but occasionally you examine, you hear about the tensilent test, okay, how does the tensilent test work?

The tensilent test is basically a test that involves the administration of a drug known as edrophonium, okay, edrophonium is an acetylcholine esterase inhibitor, okay, so when you administer edrophonium, you inhibit acetylcholine esterase, you levels of acetylcholine build up, and those can outcompete the auto-antibodies that are parked on the surface of the acetylcholine receptor, okay, so edrophonium will improve the symptoms of myastinia gravis transiently, it's a short actin, acetylcholine esterase inhibitor, so most times for myastinia gravis, you just go ahead and give pyridolstigmin, pyridolstigmin is a longer actin acetylcholine esterase inhibitor that also has the ability to cross the blood-brain barrier. Now, one weird thing they can do on the USML Es, is to say that weight, a person has flasid paralysis, right, they have like a myastinic presentation, but you administer edrophonium and those people's symptoms fail to improve. Who could be the reasoning behind that?

I'll let you think for a second, so think more upstream, what's the real limit, what's the enzyme that helps you synthesize acetylcholine, right, that's chat, okay, colon acetylcholine transfer, if you have a chat deficiency, you'll never be able to make acetylcholine, if you don't make acetylcholine there is nothing that you can put in the colonergic synapse that you will try to boost levels of bienhebidin acetylcholine esterase, okay, so if you get a question about a person that has a myastinic presentation, okay, but their symptoms do not improve with the administration of edrophonium, the very first thing you probably want to think about on the exam is a chat deficiency of colon acetylcholine transfer, deficiency, okay, so another thing that ties in with the inhibition of acetylcholine esterase is organophosphate poisoning, okay, so they may frame this as a bio terrorism question or they may frame this as a question about a kid that played in a farm that was recently sprayed with pesticides because pesticides, a lot of them contain organophosphates, organophosphates in inhibitor acetylcholine esterase, right, so by inhibitor acetylcholine esterase you have a very high buildup of acetylcholine and they can cause a colonergic toxic drop, okay, so a person will be like hypotensive, they'll be pretty cardiac because remember acetylcholine slows conduction through the EV node, if you have enough sloyne of conduction through the EV node, you can actually have like a hard block, okay, those people will sweat a lot because remember your sweat glands are responsive to acetylcholine through moscarinic receptors, although remember that that entire system is under the control of your sympathetic nervous system, right, remember that's one of those oddities about the sympathetic nervous system where it actually works with acetylcholine through moscarinic receptors.

Now you could also have like urination, right, because your presence in pathetic nervous system wants you to urinate, you would have like fickle in continents, you would have like remission, so like these people are like leaky from everywhere, if you see that, think about a colonergic toxic drop, okay, another thing that can cause that colonergic toxic drop is nerve gas, right, so like siren, siren works by inhibiting acetylcholine esterase, right, so real quick, how do you treat a colonergic toxic drop, right, you treat a colonergic toxic drop by giving something that blocks moscarinic receptors, right, so you can give a drug like atropine, atropine is a moscarinic receptor antagonist that can be used in the acute treatment, or I guess as a rescue agent in a colonergic toxic drop.

In addition, you also want to give a drug like pre-adoxine, pre-adoxine helps you regenerate, it's in the hospital, I believe it's known as two-pan, it helps you regenerate acetylcholine esterase, right, so that you can break down that excess acetylcholine, right, because there is not many, I just probably don't talk about this, I have some ideas in my head about nicotinic acetylcholine receptors, but that's more anesthesia domain, so I think I'll just sort of let go of that, I'll make some mention of that when we get to anesthesia from ecology, I'll make a podcast on that, okay, so I think we should probably go ahead and stop here, I will continue autonomic pharmacology in an next podcast, and we'll just go through it step by step, if we're listening to all these podcasts, you should become an expert in autonomic pharmacology by the end, and you should probably know all you need for your USMLA exams, so I wish you all the best, have a wonderful evening, and God bless, thank you.

It is an alpha-2 agonist, decreasing norepinephrine release at the adrenergic synapse.

Blocking $\beta_2$ receptors can cause severe bronchoconstriction and trigger airway compromise.

Bisoprolol, Carvedilol, Metoprolol (B-C-M).

Acebutolol or Pindolol.

1) Consuming preformed toxin (e.g., rancid goods); 2) Ingestion of contaminated material. The toxin cleaves SNARE proteins, blocking A Ch release.

Cholinergic transferase (ChAT) deficiency, indicating an inability to synthesize acetylcholine.

Alpha-2 agonists (e.g., Clonidine); rebound hypertension upon abrupt cessation.

Methyldopa.

Parathyroid (hypercalcemia), Pancreas (glucagonoma), Pituitary; Glucagonoma.

Myorelone.

1) Decreasing NE release; 2) Reducing A Ch synthesis/release at the ciliary body, thus decreasing aqueous humor production.

Acetylcholine (A Ch).

Alpha-2 agonists (e.g., Clonidine); rebound hypertension upon abrupt cessation.

Methyldopa.

Parathyroid (hypercalcemia), Pancreas (glucagonoma), Pituitary; Glucagonoma.

Myorelone.

1) Decreasing NE release; 2) Reducing A Ch synthesis/release at the ciliary body, thus decreasing aqueous humor production.

Acetylcholine (A Ch).