DIP Episode 18 - Autonomic Pharmacology Part 1

Okay, welcome. My name is Divine. I am a fourth theoretical student. In today's episode of the Divine Intervention Podcasts, we're going to begin to review autonomic pharmacology. It's super super high yield for step one, for step two CK, I'll almost imagine step three. And I'm also pretty sure it's something that you will encounter pretty frequently on the wards. So it's just one of those things you want to get down. And if you're also doing an anesthesia rotation, this will also be a useful topic. And because of the volume of material involved, I'm not going to talk about everything in this one podcast. I'll probably break them up into like two or three podcasts to make sure that we really get this down as well. In fact, today's goal is primarily to go over autonomic physiology. And then I'll begin to introduce the drugs that act on the alpha-adrenergic system. And then we'll take off from the other drugs that with other podcasts. So let's begin. So we know that the nervous system, right, there is at least for the efferent nervous system if you may. We have a somatic system and an autonomic system. The somatic system, we know that to be a one-year-on system, okay, and it's actually under voluntary control. And basically, the way the system works is it sort of starts in the motor cortex, okay, the precentral gyres, okay, and then it comes down as the corticospinal tract, which decusates at the level of the medallary pyramids.

And then those fibers continue on to the ventral horn of the spinal cord, okay, remember the ventral horn is anterior, and that's where alpha-modo neurons begin, okay. And then those alpha-modo neurons then continue and then synapse on skeletal muscle. And they actually release a serocoline that acts on the nicotinic receptor, the NM, M-AZN, MOBI, or whatever, okay, the NM nicotinic acetylocoline receptor, okay. And please do not confuse these NM receptors with the NN, so N is enancy, NN receptors that you find that on the cell membranes of the post-ganglonic neurons in the autonomic nervous system, okay. Now just some high-yield integration pathology here. A classic board question is one that involves spinal muscular atrophy. It's also known as a wernighoffman disease, okay. It's an otosomoroscessive disease where you basically destroy neurons in the ventral horn of the spinal cord. I remember the pathophysiology involves a mutation in the survival motor neuron 1 gene on chromosome 5, okay, it's an otosomoroscessive disease. The classic description is a baby that is not meeting motor milestones and this baby is almost always like six, seven months on exams and the baby will have tongue faciculations, okay. If you see a baby with tongue faciculations, you should have a very good reason to not pick spinal muscular atrophy.

If you, and just as an aside, if you saw tongue faciculations in a pessing that is older, like an older patient, think more about ALS, okay, Lugeric's disease. And don't forget that with snout virus and polio virus can also kill alpha motor neurons. Okay, so now we've talked about the somatic nervous system. Let's talk about the autonomic nervous system, okay. The somatic nervous system we said was a one-neuron system. The autonomic nervous system is a two-neuron system, okay, and it includes the sympathetic and the parasympathetic nervous system. Now, the sympathetic nervous system, it's called the thoracol lombar system because it runs from T1 to L2, okay. It basically originates in the lateral horn of the thoracic spinal cord, okay. And the thing is the ganglia that relate to the sympathetic nervous system, they are very close to the vertebral bodies. In fact, they are classically known as the parasympathetic ganglia, okay. So if the ganglia that contains the cell bodies of the post-ganglionic neurons are close to the vertebral bodies, that should tell you that the neurons that lead to them or the pre-ganglionic neurons have to be short, okay. So the sympathetic nervous system has short pre-ganglionic neurons and long post-ganglionic neurons because those neurons have to travel all the way from the ganglia that are juxtaposed to the spinal cord and then they have to travel all the way to the organs of interest, okay.

Now, in general, at the pre-ganglionic neuron, the short pre-ganglionic neuron, it releases a serocoline that acts on the NN nicotinic receptors on the post-ganglionic neurons, okay. And then the post-ganglionic neurons release noripinephrine, not epinephrine. Epinephrine is not what is released at these synapses. I'll talk about epinephrine in a bit, but the thing you actually release is noripinephrine. So, my epinephrine is released from the long post-ganglionic neurons, okay, any axonadrenergic receptors. Although that is not always true. The sympathetic nervous system has to other derivatives, right. So, in your sweat glands, for example, right, so if your sweat gland is a target organ, the post-ganglionic neurons in the sympathetic nervous system actually release a serocoline, okay, which acts on mascarinic receptors. That is why sweating is one of the antecedents that are observed in the setting of colonurgica over activation. So, it's, it releases a serocoline act on mascarinic receptors in the target organ's sympathetic nervous system for the sweat glands, okay. It's not always an allergic receptors. Alternatively, the post-ganglionic neurons in the sympathetic nervous system can also release dopamine, okay, dopamine acts on different kinds of receptors at different doses, right.

So, at low doses, it acts on dopamine D1 and two receptors, at medium doses, it acts on the bitter receptors, right, so beta 1 and 2, and then at high doses, it acts on alpha 1 and 2 receptors, okay. Easy way to remember that is you're going from low to high, okay, and then you're going from a later alpha bet to an earlier alpha bet from D to B to A. Now, for the parasympathetic nervous system, think of it as being the cranial sacral system. It's called cranial sacral because it originates with the cranial nerves, three, right, oculumurone nerve, seven, that's the facial nerve, nine, that's the glossopharyngeal nerve, and ten, that's the vagus nerve, okay. And it goes with S2 to 4. And remember that the vagus nerve, its innervation ends at the, at the left collic fracture, and also known as the spritic fracture. Now, in the parasympathetic system, the ganglia that contain the cell bodies of the post-ganglionic neurons, okay, they actually lie in the walls of the target organs, okay. So, that should tell you that, oh, if the initial fibers have to get to those, the walls of those organs, those pre-ganglionic neurons have to be locked, okay. So, in your parasympathetic system, you have long pre-ganglionic neurons and short post-ganglionic neurons, okay. So, an example of a parasympathetic nerve ganglia is your, your, your, your, our backs and myseness plexi in your GI tracts, okay. Those are examples of ganglia, right.

So, again, they will need long pre-ganglionic neurons to sort of feed them. And the thing is, the long pre-ganglionics, they release a cello-coline that, again, acts on NN, nicotinic acetylocoline receptors, okay. On the surface of the short post-ganglionic neuron. And just as a general principle, just remember that in the autonomic nervous system, the pre-ganglionic neurons, regardless of where they come from, be it sympathetic or parasympathetic, always release acetylocoline that acts on nicotinic receptors. So, and then, in the parasympathetic system, the short post-ganglionic neurons, they release acetylocoline that then acts on muscarinic receptors, okay. Now, a quick word on dopamine, right. So, dopamine, we said that it can be released by post-ganglionic neurons in the sympathetic nervous system, okay. One classically tested exam factoid, relating to dopamine, is that there are receptors on the afrin material of the nephra, okay. And the thing is, when dopamine acts on those receptors, it actually causes a dilation of the afrin material, okay, to increase renal profusion, okay. So, there's a drug that performs this is known as phenodopam, okay. It's a dopamine receptor agonist. You basically give it a low doses in the setting of shock so you can activate dopamine receptors in the afrin material, and increase renal profusion, okay.

But one thing you should think about is that, yes, this is theoretically true, but so it's supposed to like protect the kidneys because it's increasing renal profusion in the setting of shock. That's a theoretical trism, but it's not been proven in many studies. In fact, I was saying general in the ICU literature, this has largely been discredited. So, I'm just mentioning this for the purposes of, oh, if it shows up on in your world or on a step one exam, you're not faced by this, but it's largely been disproven by many studies, but it's just something to keep in mind. Now, another special mention here is with the Adrenal Medulla, okay, so remember the Adrenal gland contains a cortex and a medulla. The cortex has the glomerulosa that secrets out of theostero, aminolycoticoids. The cortex also has the zona fasciculata that secrets a glucocorticoids, and then the zona reticularis that secrets a sex steroids, okay. But there's also a medulla to the adrenal gland that contains cells known as chromafin cells, and it's super high yield for you exam to know that those cells that derive from neurocrest, okay. Now, these chromafin cells are actually a modified kind of post-ganglionic sympathetic neuron, okay. So, if they're a modified kind of post-ganglionic sympathetic neuron, it should then make some sense that these fibers have nicotinic acetylcholine receptors on their surfaces. That's a very high yield factor you want to know for your exam.

And these cells, instead of releasing neuropenephrine, they do in fact release epinephrine, okay. The reason that they release epinephrine is that the adrenal medulla expresses an enzyme known as PNMT, okay. PNMT converts neuropenephrine to epinephrine, okay. So, because the adrenal medulla is like basically the only high yield part of the body that expresses this enzyme, that's why you make epinephrine specifically in the adrenal medulla. And some quick things about PNMT. PNMT actually depends on SAM, S-a-denocel methyonine as a cofactor, okay. Because the one, the big difference between neuropenephrine and epinephrine is actually a methyl group, okay. And we know that SAM is a methyl carrier, okay. So, I just decided to include that as a nice biochem tie-in for you there. Another thing about PNMT is it's actually activated by cortisol. So, this is one of the ways cortisol has a permissive effect on the sympathetic nervous system. That's why patients get hypotensive when they have some kind of steroid crisis, right. Where they have like an adrenalin in sufficiency. Now, one high yield integration with this is let's assume you get an example question about a person that has Crohn's or some kind of autoimmune disease. Where they've had to take steroids chronically, okay. And then they tell you that, oh, this person goes in for surgery or they have like, they're septic, like they have like a really bad sickness.

And then they become profoundly hypotensive and they say you keep giving these people pressures, you give them IV fluids and they are not responsive, like their blood pressures are not rising. Think about administering stress dose of steroids, okay. Because remember cortisol is a stress hormone and if you're on the ghost-stressful event, like say for example you're taking step one, you put a little more cortisol than normal, right. So, if those people have been taking exogenous glucocorticoids and they are HPA access, right. So, the adrenal axis has been suppressed chronically. Those people in the setting of extra stress, they can make extra cortisol or whatever to keep their buddies going, okay. So, those people require higher than normal doses of steroids to tighten them over those stress periods if you may. So, just something to keep in mind. Now, so now we've mentioned that. Let's talk about ion channels, okay. Ion channels. So, ion channels, there are two kinds, okay. And those two kinds are differentiated by what gets those ion channels going. So, there are ion channels that are voltage-gated, right. So, a change in the membrane properties of a cell is what activates those ion channels. An example of the voltage-gated ion channel is a voltage-gated calcium channel that exists on presynaptic neurons, okay. So, when an actual potential travels down on neuron, it causes a depolarization when the membrane voltage changes, then those calcium channels activated, okay.

And then calcium can come in and cause the exosytosis of neurotransmitter from vesicles. That's an example of a voltage-gated ion channel. And it's very high, you know, that that voltage-gated calcium channel that is found on presynaptic neurons can be attacked by auto-antibodies, with a disease known as a Lumberid etymiaesthenic syndrome. It's a relatively common, or I guess a commonly tested exam, fucked or relating to small cell lung cancer as a perineoplastic phenomenon. And then the second kind of ion channel is a ligand-gated ion channel, okay. So, the nicotine receptor, right, we're actually calling it axon, is actually a ligand-gated ion channel, right. So, when a cell calling binds to that channel, it increases its permeability to sodium, okay. So, that then causes sodium to rush into skeletal muscle, for example, and causes skeletal muscle to fire, okay. So, that's an example of a ligand-gated ion channel. It's not changes in membrane-vote that activated. It's the binding of a ligand. And those nicotine receptors, actually, the ones that are blocked by neuromuscular blocking agents, okay. Now, the second kind of receptor that is necessary for autonomic discussion are the G protein-copyld receptors, okay. And the G protein-copyld receptors, there's three types. There's the G Qs, we'll talk about those in a bit. There's the GSS and there's the G Is, okay. And in general, you want to know the different receptors that fall under these three categories.

Well, thankfully, there's a very nice nomonic that can help you accomplish that. So, the GQ-copyld receptors, basically, the way these work is when a ligand binds to them, okay, you have an activation of phospholipic. Phospholipic can convert phosphoenocetol this phosphate, PIP2, to IP3, okay. PIP2 is actually a lipid, okay. It's found in cell membranes, okay. So, it converts PIP2, so phospholipic, it converts PIP2 to IP3, anocetol triphosphate, which actually increases the release of calcium from the endoplasmic reticulum. Or, I guess, if you're thinking about skeletal muscle, it'll be the sarcoplasmic reticulum, okay. And then, the other derivative of PIP2 under the action of phospholipic is that, diacylglycerol, okay. Diacylglycerol is something that activates protein kinase C that has some things that have to do with muscle mechanics, or talk about that in a little podcast. Now, the receptors that work through a GQ system, okay, the good nomonic that you'll learn as you're studying for step one, is cutesies have one M&M, okay. So, cutesies have one M&M. So, what does the have one M&M stand for? Well, the cutesie, right. So, the cutesie tells you like a QNSC. So, GQ uses phospholipic and involves protein kinase C, okay.

And then, the have, don't worry about the E, just worry about the HIV, and the one M&M just tells you that the histamine H1 receptor, the alpha-1 receptor, the visopressin V1 receptor, the M1 and three most carinic receptors, all walk through the GQ system, okay. Now, the next system are the GI systems, okay. Basically, GI, if a ligand binds to that receptor, you have an inhibition of a denilite cyclase, okay. Remember, a denilite cyclase is job is to convert ATP to cyclic AMP. So, if inhibited the denilite cyclase, you have less, you have reduced levels, or cyclic AMP. And you basically have reduced levels of high yield second messenger, so many operations during the cell either turned off or something, okay. So, the receptors that use the GI coupled system, and easy way to remember them is the MAC2s, okay. So, the most carinic M2 receptor, the alpha-2 receptor, and the D2 receptor. Those are the things that work with the GI coupled system. And then, basically, if you remember the GQ nomonic and the GI nomonic, you'll basically take whatever autonomic receptors you know, beyond what I just mentioned, plus the histamine and visopressin receptors, and those are the ones that function under the Gs coupled system, okay. And the Gs coupled system, when a ligand binds, you activate a denilite cyclase, you convert ATP to cyclic AMP, and then cyclic AMP can go ahead and activate protein kinase A. You see many of those signal link ascasing biochemistry.

Okay, so now let's talk about the autonomic receptors, okay. And for this podcast, we'll just focus on the adrenergic receptors, okay. So, the thing is, there are many, many functions of these receptors, but I will say if you know the functions I'm describing now, you're probably good to go on the receptors. So, alpha-1 receptors, okay. You generally find them on smooth muscle, okay. You find them in many other places, but for purposes of this discussion, let's just talk about them as being on smooth muscle, okay. And the thing is, when you activate these receptors on the smooth muscle of blood vessels, you cause a viso constriction, okay. That's one how you function to know. Another how you function to know is when you activate these receptors in the eyes, okay. You have my tris SS, right. So, that's a popular violation. Another thing is, when you activate these receptors on the bladder neck, okay, like the urenauris fincter, you get a constriction of the urenauris fincter and you basically have urenauris retention because the pee is not going anywhere, okay. So, high-out function for the alpha-1 receptors, okay. Activate on blood vessels, you get viso constriction. Activate in the eyes, you get my tris SS, that's a popular violation. Activate on the bladder neck, you get constriction of the urenauris fincter and urenaur retention, okay. That is all you probably need to know about alpha-1 receptors. Now, alpha-2 receptors, right. So, the GI couple, okay.

So, it's an inhibitory system. I sort of think of these as a negative feedback system for the sympathetic nervous system, okay. So, when you activate them, you basically decrease the release of meripinephrine, okay. So, activation of these receptors prevents the release of meripinephrine from the presynaptic neuron, okay. So, that's all you probably need to know about alpha-2. Now, let's jump to beta-1, okay. Beta-1 receptors, you find them largely on the heart and the afrin material, okay. When you activate these receptors on the heart to increase heart rate, right. So, a positive chronotropic effect, you increase contractility, that's a positive anotropic effect, and you also increase the speed of conduction through the AV node, okay. I'm just giving you the functions here. If you learn these functions, then it's not the drug information is much easier to remember, okay. Much easier to remember. Now, when you also activate the beta-1 receptors on the juxtaglomerulus cells at the afrin material, you also increase the release of rene, okay. Which gets the rene and your tensin, our dose-truine system. Now, for beta-2 receptors, you can think of the beta-2 receptors as being a dilating receptor if you may, okay. The higher your functions you want to know is if you activate this receptor in the early, okay, you cause bronchodilition, okay. So, that's a dilatory effect. If you activate these receptors in blood vessels, you get visodilation. Again, that's another dilatory effect.

Because basically, the beta-2 receptors, they work through a GS coupled system, they increase your levels of cyclic AMP. And one principle, I guess you can sort of commit to memory at this point is high levels of cyclic AMP in smooth muscle, not skeletal cardiac, in smooth muscle causes relaxation, okay. You'll see many applications of these principles in our multiple podcasts. But when you activate beta-2 receptors, GS coupled system, you cause smooth muscle relaxation. So, in the early, you can get bronchodilation, in your blood vessels, you can get visodilation. In the uterus, the smooth muscle that makes up the myometrium, you actually get a relaxation as well, okay. That's why, uh, tocolidics, uh, drugs like reedodrine and tributylene, which are beta-2 agonists, uh, can be used to delay labor by, uh, causing relaxation of the smooth muscle that constitutes the myometrium. So, again, just real quick, because this is super, super high yield. Alpha-1 receptors, three high yield functions. Activate them on smooth muscle of vessels, you get viso-construction in the eyes, my dry asses, all-pubulinary dilation, in the bladder, contraction of the urinary sphincter. So, you retain urine. For alpha-2 receptors, you activate them, you decrease the release of an repineffring in the sympathetic nervous system. For beta-1 receptors, you activate them in the heart, okay. You increase heart rate, contractility, and speed of conduction through the EV note.

In the GG cells that constitute the afran material, you increase the release of reenin. For beta-2 receptors, okay. When you activate them in the early, you get brunco dilation, in blood vessels, you get viso-dilation, smooth muscle of the myometrium, you get relaxation of the uterus, okay. So, the atocolidics. Okay. So, um, and I will say more about these receptors in future podcasts, especially as we talk about our different systems, okay. So, let's talk about some drugs that act on alpha-1, the alpha-1 R system, okay. So, let's talk about the agonist first, and then we'll talk about the antagonists. And the thing is, I won't just straight-up give you drug names. I will give you the ways this information is classically tested on exams, right. So, the alpha-1 Agenists, the first one we'll talk about, we'll talk about a pseudo-ephedrine and a effedrine, okay. Again, like I said, the alpha-1 receptor agonists, okay. And the primarily used to treat hypotension, right. So, if, for example, they give you a question about a person that gets an IV anesthetic, like a proper fall, for example, and then the person becomes hypotensive. In general, the answer choice you want to pick on the exam as a reversal agent of the hypotension, if you may, is, uh, is an alpha-1 agonist, like a pseudo-ephedrine or effedrine, okay. Very commonly used in the world of anesthesia. You can also use these drugs as nasal decongestants, right.

Because, again, by activating those alpha-1 receptors, you visualize or constrict the vessels that feed the nose, okay. So, you're sending, there's less blood flow to the nose. So, the nasty, goopy stuff that makes up your mucus. You're, because remember mucus is sort of kind of an ultra-fuel trait of blood, if you may, although it includes some other stuff, but we're not going to get into those details. This is not an immunology podcast, but by decreasing blood flow to the nose, you're making a less mucus, okay. So, you exert an anisode-congestive effect. Okay. And now that we're talking about this, you can actually make some pathological integration here with cocaine, okay. The thing is, cocaine prevents the reoptic of norepinephrine, okay, at the adrenergic synapse. So, you have higher levels of norepinephrine. So, the thing is, if you keep using cocaine chronically, you have very high levels of caracolomines, like norepinephrine, and you get viso-constriction of the vessels that feed the nose, okay. You can get nizzleschemia, and your nizzleseptam can actually pepper it, okay. In fact, that's a common exam question relating to cocaine, okay. That's one of the mechanisms behind that nizzleschemia from alpha-1mediated, a viso-constriction, okay. And just as an aside, if a person is intoxicated with cocaine, do you want to give them a beta-blocker on an exam?

I really hope you're saying no, okay, because by doing that, I remember that beta-2 receptors cause visodilation, okay. So, if you give a beta-blocker, right, you block beta-1 and 2 receptors, you're basically blocking the visodilitary effect of beta-2 receptors. So, you have on a post alpha-1 activation, which can cause viso-constriction, cause a nasty hypertension, and the person's blood pressure can even right higher, okay. So, cocaine overdose, never, never, never, never, never, or cocaine intoxication, I guess. Never, never, never give a beta-blocker, okay. The first line treatment on your exam is actually a benzodiazepine, okay. So, you give a benzone for the treatment of cocaine intoxication. So, now we've talked about the alpha-1 agonist. Let's talk about the alpha-1 antagonists, okay. The alpha-1 antagonists, it's best to think of them as being either reversible, alpha-1 blockers, or irreversible alpha-1 blockers, okay. And they will talk about some special alpha-1 blockers in a bit relating to BPH, okay. So, the reversible alpha-1 blockers, they can easily test this in the context of mechalismenting kinetics, okay. So, because they are reversible, okay. If you think it in terms of mechalismenting kinetics, your VMAX should not change, okay. But your KM should increase, because you're having less affinity of a regular agonist for that receptor, okay. The drug here is a phentoolamine, okay.

Now, for the irreversible alpha-1 antagonist, the drug you want to think about is phenoxybenzamine. And if you're thinking about this again in the context of mechalismenting kinetics, your VMAX should decrease, because you're taking actual enzyme out of commission, where your KM should stay the same, okay. Your KM should stay the same. Now, an integration of this with pathologies with a fiochromocytoma. Remember, this is a tumor that secrets a chatecolomins. It has a classic association with the MEN syndrome, okay. It also has an association with neurofibromatosis type 1, okay. So, just something to keep in mind. So, fiochromocytoma, the classic presentation is episodic headache and hypertension, okay. Now, if you want to do surgery, right, to remove the mass, okay. The thing is, as you're doing that surgery, if the mass explodes or chatecolomins leaks from the mass, you can have very, very nasty hypertension and prison can like die. So, in general, before those people go for surgery, you pre-treat them. So, how do you pre-treat them? You give them some adrenergic agents, okay. Actually, multiple adrenergic agents, but the multiple adrenergic agents, you give them has to be given a specific order, okay. And this specific order is the meat you want to know for your exam. The thing is, in general, you want to block alpha-1 receptors first, okay. And then you block beta receptors, okay.

The reason you want to block alpha-1 receptors first is that again, you want to take that alpha-1 medire viso-constriction out of commission before you then go after the beta receptors, okay. The reason you still block the beta receptors is, remember that chatecolomins can act on beta-1 receptors and in severe link, here's your heart rate and our contractility, okay. So, you block alpha-1 receptors first and then you block beta receptors, okay. So, again, you block alpha-1 receptors first because you want to avoid hypertension, okay. And then you block beta-1 receptors to decrease the super-increased cardiac output you can get with super activation of beta-1 receptors on myocardial. And you can actually use phantolamine or phenoxybenzamine for the alpha blockade, okay. The treatment of a phial. Now, another integration with these alpha-1 blockers is with BPH benign prosthetic hyperplegia, right. So, obviously, it wouldn't be a 30-year-old that presents with this on an exam, right. It'll be like a 70-year-old guy has trouble urinating, has urinary dribbling, whatever. And remember, I said that alpha-1 receptors, you find them at the urinary sphincter at the bladder neck. If you activate them, you cause constriction of that's fincter and urinary retention. So, a person has BPH, you want to block those alpha-1 receptors, because now open up that urinary sphincter and it can give a temporary relief of their symptoms, right. So, they can be better, okay.

So, the drugs, you can give here that alpha-1 blockers include drugs like they're your zosen drugs, okay. So, drugs like prazo-sene, doxazosen, tam-sul-terazosen, they're all drugs that can open up that bladder neck. And another drug you could give is tam-sulosen, okay. And this is why tam-sulosen is actually high, you know, apart from those other three. The thing is, it specifically blocks the alpha-1 AD receptors, which you'll find at the bladder neck, but you do not find in blood vessels, because the thing is, if a person has BPH, yes, you give them like prazo-sene, for example. Yes, you are opening up the bladder neck, but you're actually also blocking alpha-1 receptors in their blood vessels, so those people will get hypotensive, okay. They could get like an orthostatic hypotension if you make from that. So, if you just want it to be more specific for the bladder, you could give tam-sul-sene, tam-sul-sene, blocks the alpha-1 isoform, the alpha-1 AD subtype that is found specifically at the bladder neck, okay. But if a person had BPH and hypertension on your exam, giving them a drug like prazo-sene, doxazosen, or terazosen, all very good options, okay. Now, one other thing I will say is, for BPH, you should be able to contrast the difference between giving a drug for the immediate relief of symptoms with a drug for the long-term relief of symptoms, okay. So, for immediate relief of symptoms on your exam, you want to give an alpha-1 blocker, okay.

But for long-term treatment of BPH, okay, you want to give a different kind of medication. So, here's the reasoning here. The thing is, dihydrotestosterone DHT, okay, encourages the growth of the prostate, okay. So, if you wanted to prevent a person's prostate from growing or basically wanted like the prostate to like atrophy, if you may and shrink, one thing you can do is to give is to try to pharmacologically lower person's levels of DHT. The thing is, DHT comes from testosterone, the enzyme that makes that conversion is five offer-educties, okay. So, you could already predict that you could give a five-offer-educties inhibitor like finasteride or deutasteride to inhibit five-offer-educties, make less dihydrotestosterone, and effectively decrease the production of DHT and that can actually shrink the size of the prostate, okay. It's used as long-term treatment for BPH, okay. So, just something high you to know there. Now, another quick thing is these alpha-1 blockers, right. Again, if you notice, I'm not just giving you drug names here, I'm just trying to tell you, okay, this is the way they will test this, this is the way they will test that, okay. The thing is, alpha-1 blockade causes dilation of your blood vessels, right. So, you get vasodilation, so you could get orthostatic hypotension from that.

Now, the thing is, one common, I guess, physiology they test on exams, I guess from a college they test on exams at drug interactions between drugs that have vasodilatory effects, right. So, one thing they could do is they could give your patient, they give you their drug history, and they already take one medication, that's a peripheral visodylidator, and then they say which of the following medications are contraindicated, right. Because the thing is, we know that peripheral visodylators cause orthostatic hypotension, so if you combine that with another peripheral visodylator, you could cause profound hypotension that can cause like a syncopal episode, okay. So, you want to avoid that. So, the classic drugs you don't want to combine with an alpha-1 blocker on exams, okay. Include drugs like your phosphodistory is five inhibitors, like a cell-denafil, tidalafil, right. So, remember cell-denafil, that's viagra. In fact, if you pay attention to the viagra ads, you'll see that they say, oh, viagra should not be taken in a person that also takes nitrates to prevent an unsafe drop in blood pressure, right. So, they include that warning because nitrates are also visodylators, okay. Remember, your PD5 inhibitors use them for pulmonary hypertension, but you can also use them for erectile dysfunction, okay. Now, you also want to avoid alpha-1 blockers with hydrolyzing, okay. Quick word on hydrolyzing, right. So, hydrolyzing is a visodylator, right.

That's why you don't combine it with an alpha-1 blocker, but one of the commonly tested factors with hydrolyzing is that its mechanism is that it dilutes pre-capillary materials, okay. So, remember, your arteries, they become materials and then those materials form capillaries and then those capillaries form venials, okay. Hydralizing works by diluting pre-capillary materials and think about it if you dilute a pre-capillary material, you increase in blood flow to capillaries, okay. And if you increase blood flow to capillaries, you increase in, if you're thinking in terms of your starting forces, you increase in the, the hydrostatic pressures in those capillaries and that can increase the extroversition of fluid. That's why you could classically get a dima as a side effect with hydrolyzing, okay, because you're increasing hydrostatic pressures in capillaries. So, if we know that increasing the hydrostatic pressures in capillaries is the mechanism behind a dima with hydrolyzing, we can try to counter that effect by dilating the post-capillary venials, right. So, if you dilute the venials that drain the capillaries, you decrease the hydrostatic pressure and you directly act against the pathophysiology of the dima, right. So, the classic high-yout post-capillary venial diliterated, you want to know for your exam, the ACE inhibitors, okay. Your ACE inhibitors, they can dilute those post-capillary venials and treat the dima that's associated with hydrolyzing.

As you'll see, this dima from dilation of pre-capillary arterials is another high-yout side effect with your dihydroperidine calcium channel blockers, like amlodipine, phyloidipine, and stuff like that, okay. So, hydrostatic pressure, that's one high-yout factor you want to know. Another high-yout hydrostatic pressure is that it's safe in pregnancy, okay. So, you can use it to treat hypertension in pregnancy. The other drugs that are safe in hypertension in pregnancy, the mnemonic for those is hypertensive moms love myfidipine, okay. So, the H-stance for hydrolyzing, the M-stance for methyl-duper, duper, okay. The L-stance for labidolol, okay, and the M-stance for myfidipine, okay. So, something to keep in mind there. Another high-yout factor with hydrolyzing is that it can actually cause drug-induced lupus, okay. Remember the association there with anti-histone, antibodies. In general, if you stop the drug, the lupus will go away. And one weird factor to just sort of keep in mind is patients that have drug-induced lupus, they tend to be slow acid leaders, okay. Slow acid leaders. So, just sort of keep that in mind. They usually test that factor in the context of an isoniazid. So, again, avoid an awful one blocker with hydrolyzing. Another drug you want to avoid with an awful one blocker is an endothelian receptor antagonist, like Bocentan or Ambracentan. Remember that those drugs are used in the treatment of pulmonary hypertension, okay. They are visodylidors.

You also want to avoid an awful one blocker and minoxidil, okay. Minoxidil, the way it works is it's potassium channel opener, okay. So, it causes hyperpolarization and the smooth muscle relaxation. Again, you want to avoid giving that drug with an awful one blocker because it's a powerful visodylidor, okay. But some other high-yield things with minoxidil. Minoxidil is actually contraindicated in diabetics, okay. The reasoning behind that is, remember, if you're diabetic, you need as much insulin as you can, okay. The thing is insulin is released when the beta cells of your pancreas depolarize and the depolarize by the closure of potassium channels. So, if you give a drug that's a potassium channel opener, like minoxidil, okay, you basically make your beta cells of the pancreas not depolarize, okay. And if they don't depolarize, they will be less insulin release, okay. In fact, that's why minoxidil is generally contraindicated in diabetics. And the thing is, there's a drug that also sort of works like minoxidil is known as diazoxide. Diazoxide is a potassium channel opener and it's actually used to treat an insulinoma, right. So, an insulinoma is a tumor, classically with the MEN1 syndrome, that secretes a ton of insulin, right. So, if you hyperpolarize those beta-1 cells in the pancreas, you could decrease the release of insulin and you could potentially treat an insulinoma.

Finally, with minoxidil, another thing you want to remember is that it can be used to treat a meal patterned baldness. In fact, it's one of the, it's the branding for a minoxidil. Now, another set of agents you want to avoid with the alpha-1 blockers, drugs like your prostacicline analogues, like troprostinial, ilopros, type of prostinial, again. These are good viso-diilators. And then, finally, you also want to avoid the alpha-1 blockers with your dihydropyridine calcium channel blockers, right. So, like I'm low-depping, for example. And remember that those dihydropyridine calcium channel blockers, they work by also, again, diluting pre-capillary adherence, okay. So, that's where I'm going to stop today. If you have any questions or spot any errors, feel free to make a comment to this podcast or send me an email, divineinterventionpodcast.gmail.com. And I wish you all the best, have a wonderful week, and I'll see you in the next podcast. Thank you.

They always release acetylcholine (A Ch) acting on nicotinic (Nn) receptors on the post-ganglionic neuron.

PNMT (Phenylethanolamine N-methyltransferase).

$G_q$ (Phospholipase C $\rightarrow$ IP3/DAG); $G_i$ (Inhibition of Adenylate Cyclase $\rightarrow$ cAMP $\downarrow$); $G_s$ (Activation of Adenylate Cyclase $\rightarrow$ cAMP $\uparrow$).

Cocaine causes $\alpha_1$-mediated vasoconstriction, leading to nasal ischemia and septal perforation.

Because blocking $\beta$ receptors removes the vasodilatory effect of $\beta_2$ stimulation, leaving only unopposed $\alpha_1$ vasoconstriction, which can cause severe hypertension.

Sympathetic has short pre-ganglionic fibers and long post-ganglionic fibers; Parasympathetic has long pre-ganglionic fibers and short post-ganglionic fibers.

Chromaffin cells (derived from neuroectoderm) release NE, which is converted to Epi by PNMT, an enzyme that requires SAM as a cofactor.

The receptors are Histamine H1, $\alpha_1$, V1 (Vasopressin), M1, and M3.

They inhibit 5-$\alpha$-reductase, thereby lowering testosterone conversion to dihydrotestosterone (DHT) and promoting prostate atrophy/shrinkage (long-term management).

Other peripheral vasodilators, such as PDE-5 inhibitors (e.g., sildenafil) or nitrates.

Voltage-gated calcium channels ($\text{Ca}^{2+}$).

They prevent the depolarization required for insulin release from pancreatic beta cells, potentially leading to hypoinsulinemia.

Chromaffin cells (derived from neuroectoderm) release NE, which is converted to Epi by PNMT, an enzyme that requires SAM as a cofactor.

The receptors are Histamine H1, $\alpha_1$, V1 (Vasopressin), M1, and M3.

They inhibit 5-$\alpha$-reductase, thereby lowering testosterone conversion to dihydrotestosterone (DHT) and promoting prostate atrophy/shrinkage (long-term management).

Other peripheral vasodilators, such as PDE-5 inhibitors (e.g., sildenafil) or nitrates.

Voltage-gated calcium channels ($\text{Ca}^{2+}$).

They prevent the depolarization required for insulin release from pancreatic beta cells, potentially leading to hypoinsulinemia.