Lecture 2 -2 PDF

So our normal full agonist is the red curve. Now, if we introduce an irreversible competitive antagonist And I know that sounds That probably sounds a little contradictory to what I just said, but that would be The same as your same as non-competitive. They just called it irreversible competitive...

So our normal full agonist is the red curve. Now, if we introduce an irreversible competitive antagonist And I know that sounds That probably sounds a little contradictory to what I just said, but that would be The same as your same as non-competitive. They just called it irreversible competitive for whatever reason. But that's the same as your non-competitive antagonist. So if you add that into the mix and you have both of those kind of floating around in the serum or in the tissue You can see how that curve now changes. You've lost efficacy. And you've lost potency. By putting that non-competitive antagonist in there. If, on the other hand, you put in a competitive antagonist Now you've lost potency But your agonist can still have a full effect. If that makes sense. You're basically just competing And so now your agonist is not as You would need way more of that to help compete with the antagonist that's floating around. So that's why the potency is dropped If you get some of that non-competitive on the receptor, it doesn't matter how much agonist you give. You know you've lost efficacy at that point. You're not going to probably occupy enough receptors and get a full response because of that antagonism. Yeah. Yeah. Dr. Elmore, before you move on. Would you be able to provide maybe a real world example of something of something a scenario maybe and maybe this is too much for an impromptu But there's… the words themselves are so similar. I'm having a hard time grasping what does what. Okay. Would you be able to provide like in the OR with a patient, we do this. And then if I give this, whether it's you know, with succinylcholine or an anesthetic or some kind of example that might help me solidify this process or why. We would want to or we would want want to do this sort of thing. I don't know if I can tell you why you want to do it, but yes, I will try to give you examples Okay. Example of a full agonist, let's say um Your catecholamines. You have a full you let's say you're pumping out norepi to stimulate your sympathetic nervous system, stimulate the heart to increase rate pump faster. That would be your agonist. Now, this is not a drug, right? It's just a catecholamine. Now let's say you give esmolol. Which is a beta blocker. You are now giving a competitive antagonist Which is in theory going to push the potency of your catecholamines across your X axis to the right. So you would have to really pump out a lot of extra catecholamine, a lot of extra norepine epi. Floating around. Near your heart in your heart in order to blot or to knock some of the beta blocker, knock some of the esmolol off of your alpha and beta receptors. Okay. To now stimulate the heart. So, you know, if you have a patient In the OR that's taking metoprolol, same thing beta blocker And now you want to give them ephedrine or something that would increase the level of catecholamines that Are coming out into the plasma you know you might find that it takes more ephedrine Or, you know, some other type of The azopressor, it's going to take more of that catecholamine to help get a clinical response because you have receptors that are occupied with metoprolol. And you need those two molecules are competing for that receptor. And it's not necessarily that it's not necessarily that all of the, you know, metoprolol is just going to go away just because there's extra NORAD B floating around. I mean, it could be that a norepi molecule comes, knocks one off Okay, we're going to start to maybe get an effect but then Depending on how much metoprolol is floating around. It may actually come back and hit that receptor again. I mean, this is obviously not a black and white scenario. It's very complex. But it actually helps. It's a much more cut and dried explanation than I was anticipating, but I'm so grateful because it does make sense. Some people take extended release metoprolol. Okay. You know, if it's an unplanned surgery then you may be fighting that effect and you're you're kind of in a kind of a battle for the same receptor Okay, that helps immensely. Thank you. Yes. Yes, you're welcome. We don't use a lot of non-competitive antagonists. So, you know, the red and green are kind of the more common that you would see maybe clinically. Another example is rock uranium. It's sitting on receptors. And, you know, on the muscle at the neuromuscular junction. In order to help reverse that effect, this is not Segamadex, but If you're using neostigmine. Stigma means basically means you know what we're trying to do is we're trying to increase the acetylcholine that's in the synapse. To compete with rock uranium. So it's going to help prevent the breakdown of acetylcholine so that we have enough agonists in that neuromuscular junction to hopefully knock rock uranium. Off of its receptor. So we do have instances where you're competing. Narcan and an opioid flame as a benzo. It's kind of the same thing, especially with Narcan. If you've ever had to like put someone on an infusion you know, obviously there's so much opioids circulating or maybe it's a longer acting opioid But there's so much in there that a single dose or maybe a repeated dose wasn't enough. You kind of have to put them on an infusion because A lot of our opioids the duration of action may be longer than the duration of action of flamazenil. Or you just need so much extra antagonists to compete with the high amounts of agonists that are just hanging out If that makes sense. No, it makes sense. So there are instances where you will kind of notice this clinically And this is just kind of what's going on mathematically or pharmacologically When you do see that. So antagonists do not activate a receptor. They don't cause a clinical response. They don't have efficacy. That's the curve. Well, it's not a curve. It's that straight line across If you're looking at a dose response. Graph. And so if we were to continuously block a cell from having the response that it wants to have, we're going to have upregulation of the target receptor that would kind of initiate a response. So here's our examples of antagonists. Competitive and aspirin's considered non- competitive. Inverse agonists. I know when I first started teaching farm, this was kind of a new concept for me. Inverse agonists are a little bit different. So if you remember the dose response curve I showed you with all four On their inverse agonist kind of dips below the x-axis So the difference here is that you basically need a cell that already has some activity that it's doing on a regular basis. So there's some intrinsic activity that the cell is responsible for And if an inverse agonist binds a receptor, it's going to Basically decrease or stop that activity. So it's going to turn it off. And we consider that having negative efficacy. Inverse agonists. It can have the same, it can bind the same receptors and agonist It can be blocked by an antagonist. It kind of responds like You know, I guess pharmacologically it behaves like other types of drugs But the effect is different. It's opposite effect of an agonist. So there are drugs that are inverse agonist. And we typically classify them as antagonists or they may have properties of both So carvetolol and propranolol are considered inverse agonists in the function of decreasing cyclic AMP. Naloxone has both inverse agonists and antagonist effects. Allosteric modulators, we will revisit these again in When we get to anesthetics. So an allosteric modulator is going to bind just like a ligand binds to a specific place on the receptor. An allosteric modulator is going to have a different site to bind to. So aloe meaning different. Cerec is just a different site. Then the site that is needed to activate the receptor. So here in this example, you have a GABA receptor. Gaba is the ligand that activates a GABA receptor. When you give midazolam. It doesn't bind the GABA receptor. It binds a different spot. It has its own binding site. And it enhances GABA's binding of the receptor and GABA's effect on the receptor. Yes, very similar. A cofactor, but not in the sense of a cofactor where a lot of times you need both to bind Obviously, this GABA receptor can have an effect, whether a benzo is on it or not. But if you have a benzo bind. You know, once GABA hits that receptor it's going to have a prolonged effect. It's going to sit open a lot longer way more chloride is going to come in than if you had gaba binding Alone. So they modify the effect of the agonist in some way. Usually we learn about positive allosteric modulator, PAM. In which like a benzodiazepine, it's going to increase the effect of GABA. They were also negative. Allosteric modulators. Drug interactions. You guys have all heard of additive effects. You know giving one drug plus another drug It's going to be the sum of the two of the two in effect. So for us, I would say giving um giving One of your anesthetic gases like SIBO fluorine plus nitrous oxide is an additive effect. I can give half of a dose of SIBO and half of a dose of nitrous and it's a full dose. Antagonistic effects, you guys all know the drug is going to prevent or block the response of a different one. Synergistic effect the sum of the two or the response from the sum of the two is greater than an additive effect. This is where I think sometimes as anesthetists is we kind of get into trouble with synergistic effects. A lot of our anesthetics, our opioids with our IV anesthetics together. Is synergistic. So if I'm doing a sedation case where I want that patient to maintain their own airway. I want them to ventilate well. I want them to maintain their own hemodynamics without me doing a whole lot because it's just a sedation case. I'm not putting an airway in, hopefully. I have to be very careful how much propofol and fentanyl And Vers said that I kind of start stacking on top of each other Because those drugs have a synergistic effect when they're merged together. And I can very easily flip that patient from ventilating well and maintaining their own airway to apneic and all of their airway tissue collapsing. Potentiation. Using one drug kind of enhances a different drug Kind of similar to the synergistic effect With potentiation, I think it's a little bit different. And the example that I have for that is the antiretroviral therapy is used for HIV and AIDS patients. A lot of those drugs are combo drugs. And work by potentiation. Would it also be like… I believe it's metoxolone, giving that 30 minutes before your Lasix Maybe. I'm not sure about that one. But look it up and let us know. That one I'm not sure about. Tachyphylaxis. We see tachyphylaxis a lot. That's when you get a decrease in efficacy following a repeat administration. This is a concept that's not fully understood. It could be that there's some contribution of pharmacokinetics where maybe where you continue to give a drug, but for some reason it's the pharmacokinetics as you continue to like flood the plasma with the drug Is there some sort of distribution through the tissues where you're not maintaining the same concentration in the target tissue? It could be pharmacodynamic. Mechanisms where You know how I mentioned if you're constantly giving a tissue an agonist And it's like, that's way too much stimulation. I'm going to now cut back my receptors. Or reduce my sensitivity to the agonist. It could be that that's happening a little more quickly, a little more acutely than you would expect. So it's not completely understood, but as you continue to give a drug We see this a lot with ephedrine. We see it a lot with phenylephrine. There are many other drugs that you can get into tachyphylaxis with. But you're just not quite getting the same response over time. I can tell you just anecdotally, I don't have like all the evidence in the world. It's not a controlled environment that i'm studying this But if I go into Another anesthetist room and give a lunch break. And I see that they have that patient on a neo drip at like 80 or 90 mics per minute. I know very well that they have probably hit tachyphylaxis. Personally, just over years like i feel like Once you get to a certain level, like a certain infusion rate for phenylephrine you really aren't seeing any additional response. So it's those patients when you're kind of on that high dose and you feel like I need this high dose to maintain and you're still struggling. It's time to get a different vasopressor out. Or do something different, change up your anesthetic or whatever. So that's something we will sometimes see. I'm not saying it always happens. But it can happen clinically. Um… Question. Yes. I have a quick question. So you said for NIO, you said 80 mics per minute In my ICU, we usually go up to 360. So does that mean after 80 don't work anymore? That's a lot. That's a whole lot. I'm just telling you what I've observed is that, you know, these high doses you know we're not always seeing any additional effect. I would imagine if you're on 360 of phenylephrine, they're also on Yeah. I don't know, vaso or epi or other things In that case, it's like, how much is the phenylephrine really contributing to the effect at that dose. Okay, thank you. So I don't know. That's why I said I'm not saying there's a lot of factors I don't No, but that's A lot. And I just from my own practice or what i've seen from Once you start getting higher and higher It's hard to say. I mean, there's a lot of different factors there i mean You know, I mean, obviously. I don't know if that's a cardiac patient or septic patient, what other mechanisms they have going on that you're trying to fight. For us, it's usually you're fighting massive vasodilation from our drugs and maybe blood loss but I think that we start to get into tachyphylaxis with high doses Like that. To me, you said adding a GABA agonist on benzodiazepine as potentiation. No, because they work on the same receptor. So that would probably just be like an additive effect, maybe a synergistic effect Do they get upset when you start changing the guts? Oh, the drips. I do not try to, I try not to change anybody else's drips. Um… Other things in the chat. Let's see. Metal, I don't even know how to say that drug metallas metallism potentiates the diuretic effect of furosemide and therefore simplifies the treatment of fluid retention. There you go. Yeah, it's one of those that we were given the MICU a lot where they're like, give this and then 30 minutes later, then you give your Lasix. So that's like, I guess, the other thing that I can think potentiate. Okay. Maybe because it's a works by a different mechanism but like really Yeah, really extends the effect. Kind of the pump, I guess. Any other questions so far? Oh, I accidentally gave you the answer. Which drug is closer to reaching the LD 50. It is drug B. In this case, because we are increasing in concentration. As we go along the x axis. On which axis would you find the C50? My chat's not keeping up. We have a couple different answers. The C50, what is the C50? It is the concentration of the drug. So it would be on the x axis. Which drug is the antagonist? Which drug is the antagonist? A couple different answers. If you said neither, you're correct. If you notice, both of them get all the way up here to a maximal effect. So they are both agonists. Which drug is more potent? Good. And which axis represents the ability of a drug to produce a clinical response? Perfect. Y-axis. Which molecule is one half of a racemic mixture. Top left, top right, bottom left, or bottom right. One half of a racemic Mix. For those of you who said top left, that is correct. With it being a If you're looking for 3D asymmetry. A molecule like this, you're going to look for four different atoms all the way around four different atoms. And that is the only one If you forgot that. Piece of trivia, you can look and kind of see what helps, you know, what might distinguish one from the other three options if you're trying to improve your test taking skills and you can see that there's two similar molecules on every other one. This is the only one that looks a little bit different in that aspect. From Valley, Memory Master, where is potency depicted on a dose response curve? Potency. X axis. I can't see those two together. So if you remember, you know, when we're moving along the x axis. It's potency. Moving along the Y. Is efficacy. How are drug potency and receptor affinity related are they is it a direct relationship or indirect relationship? Good. That's direct. The greater the affinity for receptor the more potent the drug. You're going to have a nice steep slope And it's going to be a little more on the left side. Of the x-axis. How does a dose response curve shift for highly potent drugs. Good. Looks like we got the most votes, which are correct for left shift. You might want to think of it as less drug, left shift, less drug What does the slope? Of a dose response curve represent? Related to potency If that helps. Nope. Gernan has got it. It is receptors, number of receptors occupied. Next one. What is efficacy? And what part of the curve is represented. So what is efficacy? We'll start there. Yeah, the ability to get to that maximum effect. And then what part of the curve the actual curve Good. Plateau. So ability of a drug to produce the desired clinical effect is efficacy. And it's represented by the plateau on the actual curb itself. Ld50 over ED50. Guys should all know that one. Yep, therapeutic index. Or your margin of safety. Let's see, last one, I think. How does a competitive antagonist alter the dose response curve of an agonist If you remember the chart where we had the mix of the two of the two If you put a competitive antagonist, sorry, in with an agonist, what happens to the dose response curve? Yeah, moves to the right. There's no change in the plateau, so it just moves to the right And then how does a non-competitive antagonist alter. What was the difference in those two? Yep, shifts down. So lower on the plateau And shifts to the right a little bit. So it's both. So shifts right and you have a… shifts right and down, like the plateau comes down And a little bit of a decrease in slope, which we didn't really talk about. But that was part of Valley's answer. Decrease in the slope. Because you have less receptors that you're able to bind the agonist has less receptors that it can get to. And then what is tachyphylaxis? Let's see, Nicole, what is tachyphylaxis? You're muted. Nicole. Your friends have helped you in the chat, it looks like. I can't remember. I remember it's a reduced response. In the efficacy. Okay. So, yeah. Like when you do the drug, right? Yeah, you keep giving it and you get less of a response it basically you're getting resistance. That's exactly what it is. Yeah. Dr. Elmer, I have a quick question. Well, we have to know the difference between Tachyphylaxis and tolerance for the exam. No, we haven't talked about tolerance yet. Any other questions up until this point? Um… Let's take a break. So we'll do 1110. We'll come back and finish up. 1110. Okay, I'm going to get started again. So very short section on pharmacogenetics. I already gave you guys kind of the separate video on population so Many of these slides we're going to skip over because you've already had that Pharmacogenetics It's kind of an emerging field. Where they can study some of the genetically determined variations in how we respond to drugs. Now, some of this could be related to differences in pharmacokinetics. For example, we see a lot of population-based differences in metabolism Or it can be pharmacodynamic like responses at a particular receptor or in a particular tissue might vary from person to person. So we're seeing that now that we're doing more and more you know genetic mapping for individuals we're able to kind of study this in a little more detail So that we can at some point start to improve drug selection, dosing accuracy, helping to avoid adverse effects and things like that. So it's kind of in Area called precision medicine And we're seeing as more and more in kind of like the outpatient setting, not so much necessarily in anesthesia There are times here and there are times genetics and genomics kind of come into play. Franco genomics in particular There's some variation in a genome. That can affect the ability to metabolize a drug or they may even kind of look at a tissue that's the target of a drug like a tumor And then determine what genetic sequencing and such that particular tumor would respond to as far as a chemotherapeutic. Um so That's something that's growing more and more. Population-based variability, I kind of mentioned this before, you know, a lot of the dosing that you see in a textbook has been studied in what they have been studied in what they have defined as some sort of normal population. So what do we do when we have the patient that is outside of that? Typical population? How do we change our plan of care if we have a pediatric patient, an obstetric patient, etc. So major influences on pharmacologic response and pharmacologic response and the pharmacokinetics and how we kind of move drugs are things like age, sex, weight. Body surface area, etc. Polymorphisms so generally the reason why we see differences from person to person is related to a polymorphism which is a variation in DNA sequence. One of the more common is a SNP, a single nucleotide protein. There's one nucleotide exchanged for another in a particular position. Sometimes it's an alteration in your proteins and your biochemical pathways. So for example. And our CYP450 isoenzyme system. Cyp2d6 in particular They've done a lot of research on a lot of research on ethnically different populations and ethnically how much they might vary in their ability to break down drugs that. Our targets of the CYP2D6. So if you remember 2d6 It helps metabolize drugs like oxycodone and Not necessarily as much the ones we give in anesthesia, but a lot of the ones that patients might get post-op or on their way home or something like that. For example, they found like in Caucasian populations, about 7% to 10% are poor metabolizers So they may have more of that drug kind of stick around versus Asian and African-American populations, about 30% are more intermediate And then there's Ethiopian populations that can be ultra rapid metabolizers Meaning they may really break down that drug Very, very quickly And the issue becomes really, if you think about maybe even your own practice and you've had that patient that seems to need a particular drug a little more often than You would expect or a little more often than someone else Sometimes we make these snap judgments of like Maybe they're drug seeking or something like that when we honestly don't know if there is some sort of genetic alteration that affects their metabolism. Of an opioid that you know the next patient doesn't have. So it's just, it's not something we really fully know and understand yet. I can't say that it's really going to affect the vast majority of your anesthetics but anesthetics but these are things that can happen. There are some drugs that we do know that Some populations have the capacity to metabolize that drug Very quickly. Others might be very, very slow. In that, let's see. Comments. I had my genes mapped via Mayo Clinic. You're an ultra-fast metabolizer. Very interesting. Yeah, I would imagine they would be surprised like why is this not having the effect we want it to have? So yeah, very interesting. Thanks for sharing that. Most occur in the metabolizing enzymes, like I mentioned. So we can see variability metabolism, but also absorption, distribution, excretion As well. So we also have to know that you know, when we see some of those changes, sometimes we may not know unless a patient either like Jennifer, you know, they're not responding to a drug or maybe they have an exaggerated response Maybe we've kind of moved them into a toxic level because that drug is staying around for much too long um so pharmacodynamics and drug response Obviously, like I said, we're trying to individualize therapy trying to identify the efficacy for each individual is going to affect maybe how often you give a drug, how much you give. A particular drug if we expect a certain population to have less proteins, obviously we're going to adjust our drugs based on that. But if they also have genetically based issues going on. It can also affect how they respond to a drug. There are some treatment algorithms. There's probably more than this. Than what I have here, but just some examples. Genetically based treatment algorithms that are being used as Plavix, warfarin. Beta blockers, ACE inhibitors, and statins. So you can see there's a lot going on in the cardiac world And then they've also been studying this for psych In ECT, which is electroconvulsive therapy used often for often treatment resistant depression, suicidal ideation, and other types of psych Conditions. And also just to give you one example I can think of off the top of my head for example Anesthesia is, if you guys have probably heard that if you have red hair genetics for red hair. You have much higher anesthesia requirements. And that is something you will see clinically. I gave you guys all the considerations for these, so we'll kind of go all the way to the end. The only one i did not cover is sex dependent differences. There's two additional slides at the end here. There are some hormonal differences that could potentially affect pharmacologic response or movement of drugs changes in muscle mass composition, blood flow organ function and then just a few examples of drugs and how they could potentially you might see differences based on Sex. For example. With… muscle relaxants, females tend to be more sensitive to the effects of muscle relaxants. Females tend to emerge from anesthesia a little more quickly than males. So those are some things that are those things you may notice. Any questions? Yes, Zach. Going back to like the obstetrics slide specifically neuromuscular and progesterone. You have a little a little saying in there that it's like greater risk of awareness, increased sensitivity to general anesthetics. Why does that happen because like why does that happen does the since you have like a dilated epidural space and like less like CSF there does it become systemic easier. Okay. To the note. No, this would be totally different. If they would have… So the progesterone kind of has a sedating effect So this is actually if they were to receive general anesthesia to go to sleep for delivery Which, of course, is of course is Really only reserved in case of emergency. Then if you put them to sleep, you're intubating, you're putting them on SIO fluorine they tend to need less. They're going to be more sensitive to the effects of general anesthesia because of the progesterone. That actually has nothing to do with Neuraxial anesthesia. Because we are using less general anesthetic they are unfortunately at a higher risk for awareness If you think about it, this is a little more complex, but you know if it's a true emergency There could be hemodynamic issues going on. They could be at high risk for postpartum hemorrhage. There may be other reasons why you are keeping their their anesthetic level lower than you normally would. And the idea is just that it increases their risk that they could remember what happened when they were under general anesthesia. Which is awareness. And plus, if we try not to put a patient to sleep a pregnant patient will sleep because we don't want any fetal effects as well so that's as well reduces our usually reduces the desire to give systemic opioids and and you know Even like benzos. So you're really just kind of giving minimal drugs until you get baby out, especially if there's fetal distress all of those things collectively together could increase the risk that mom would remember. What's going on? Mm-hmm. Thank you. Yeah. And one more question about the like pediatric and neonatal section under renal In the worksheet, you had the question about like what renal difference is affect their ability to eliminate drugs. And I understand the concept that they rely on the renal system more because the liver is still immature and you say it has reduced renal extraction for uncharged drugs. So that would be the lipid soluble but The renal predominantly will allow just like the ionized water soluble molecules to be excreted right So… I don't know. I guess I'm confused why you're saying uncharged drugs here versus like, shouldn't it be ionized or is it both Unchanged drugs. So remember how some drugs don't necessarily go through metabolism. So if they don't undergo any sort of metabolism, generally they're already kind of in that charged and water soluble state. So they can go straight to the kidneys to be excreted. But if you don't really have a mature kidney yet. That kidney may not really have the functionality to help get rid of that drug. As easily as a more mature kidney. Does that make sense? Yeah, so like those ionized, maybe water soluble drugs that just kind of get excreted they might hold on to because of the immature renals. Okay. Yes, because I mean, it should, you know, hopefully it would still filter across or be actively pumped across. Like, you know, if the drug molecule is too big or, you know, for whatever reason does not get filtered through the glomerulus. Can't say that word. Then it's going to kind of go into that circulation around the tubules. Then you're relying on mechanisms within the tubular cells to pump that drug into the urine filtrate. If those processes are still very immature and still developing. You may have less of that drug actively pumped into the filtrate and it may go back into circulation Does that make sense? Yeah. Thank you. Yeah. Is there a particular slide that you missed a blank on? Everything that I give you guys is fair game for testing. So if there's a particular slide you missed a Blank on. I think… Sorry, Dr. Elmore. I think there were several that um we just kind of skipped through quickly Just now. So I think that might be what she was talking about. Okay. Any other questions? On pharmacodynamics. Or population. I had one question on like pharmacokinetics sorry to kind of deviate. Yeah, go ahead. So in your notes, you were saying that propofol has a high volume distribution and then rock uranium has a low volume distribution. So low volume of distribution, I'm assuming. Or like, yeah, it'll stay in the plasma more So how does the Rocky Romium exactly get to our biophase, like where we want it to act like if it has a low volume of distribution, wouldn't it stay in the plasma more? Yeah, and it really is the kind of the reasoning or not the reasoning for it, but the take home message really for that is that you would probably have to have to have more propofol to keep it in the effect site where you want it to go. To have the effect. I mean, rock uranium is still going to get there but it's just you know, it's really more of a kind of like how does the drug move and how do we figure out how much we need to give? With propofol having a big volume distribution. I mean, it is going to easily go into the tissues, but it's going to easily come back out. So, you know, you may have to give you know a much bigger dose to get the right concentration where you need it to go. The idea with rock uronium being a little bit more water soluble in that sense is that it's just not going to travel as much. The volume of distribution is going to be quite compact So it's going to be easier to build up The level where you want it to go. It'll still make it to where it needs to go. I'm not saying that it's all water soluble. It's not going to be able to get to its receptor and have an effect. It's going to go straight to the kidney. It just means in general that drug is not going to travel into all these other tissues where it's not going to have an effect. So that's kind of the the take-home message really there, if that makes sense. I think so, yeah. So it won't travel to other tissues where it won't have an effect. Right. Thanks. Any other questions? And then did anybody have questions on the actual or a problem question that they wanted to go over. Also, another question about it. A math problem question. Elizabeth, are you talking to us? Because I can't hear you. A little bit better, yeah. Okay. Yeah. Okay, sorry. I was just, I just had a question about the exam So if we study like use your PowerPoints as a reference, use the book and to guide us kind of But basically what you have put in the slides is what we need to know. We don't need to dive into the book anymore on topics that you didn't talk about, just the ones in the slide. Or what we should focus on, correct? Right. If it's not something we didn't cover then Yeah, you don't have to dive deep into that. Not saying it's not board material possibly but then you probably won't see it if it's something we didn't cover in the In lecture. Perfect. Thank you. Sorry if that was redundant. No, you're good. As far as the exam, I haven't finished putting that together, so I will… give you guys kind of a brief announcement of what it might look like next week. So next week. At right before 9 a.m, I will put in a Canvas announcement for the password. And then you guys can jump on to exam soft take the exam and then we will all jump on a Zoom at 1030. Dr. Elmore, do you know how soon the exam will be available to download? Yeah. As soon as I'm finished putting together, but I mean, definitely before the weekend And what is that time limit? Do we get to see our grades right away or do you wait to release those? Do we have any preliminary results? No, you won't get a preliminary. I mean, as far as I know, I don't think ExamSoft gives you any kind of feedback on that. So you have to wait for me to really do an analysis and then put it in Canvas, like release the grades from exam soft into Canvas. Do you usually do that same day or like what's the timeframe that we'll know It just depends on what I got going on on Tuesday afternoon. I usually try to get it up as soon as possible. It's never going to be like a week or anything crazy it's usually fairly quick, but as far as like before we all meet at 1030, probably not. So hopefully later on Tuesday, maybe the next day Time limit for the exam is going to be based on how many questions I give you. So it will be timed. And I'm expecting between 40 to 50 questions, but I'll let you know when I get it. Completed. Is there any like expectations for the group exercise or what can we expect with it? You'll find out when we get together. Say that. Okay. Release the need to control. That's going to be my new motto for the rest of the program. Bumper stickers made and send them to all of you. No, you don't have to like prepare anything or do anything. We'll just… We'll meet and then you'll find out. What else you guys got question wise If no one else has questions, you all are free to go whenever. I'll just click through these. Few more and a few more And then that'll be it. Get you out a little earlier than I thought. I actually had one more question about the ion trapping. For the example like written in our notes and stuff, it was about basic solution. And then I think one of the practice examples was with an acidic solution. Which I was just a little confusing. How it could be trapped once it's in a acid solution because it would like hold on to its ions and stay like in the You know, acidic non-polarized form. So how could it get trapped? Is this one of the… questions I gave you. I can look. I just kind of wrote it down on my sticky note, but I'll look at part three. It wasn't a slide. I think it was from the practice questions. Or is it a particular slide or something that I can Um… Tasha, no, that's the next week. The next week after the exam, I'm sorry. I think it was problem three the weak acid And then which side wood of the blood-brain barrier would experience a greater fraction of the drug ion trapping. The plasma of the neuron. This is on the ones that I just gave you guys. Okay, well, I can pull that up. In a second here. Mm-hmm. Because like I said, I just like Through those questions together so I'll have to pull it up to see. If it's something that makes sense or not. I think how many more of these do I have? I think your spotlight has like all of these filled in for people that weren't able to fill them in. It should. Yeah. Yeah. There's also just one blank slide, Dr. Amor is obstetrics GI. Obstetrics and GI is blank. On 104. Oh, Lord. This one? This is something I need to go back and X. No, I think you just covered everything that we wanted to double check. It's… Okay. All right. Good. Let me see if I can, let me find that other Document. I have it up so I can post it in the chat, the question for us. Okay, so this is… It's number three, you said? Okay. Weak acid pKa of 9. Starts in the plasma, crosses the blood brain barrier to enter a neuron with a pH of 7.2. Oh, I was being extra. Crafty when I made that question, wasn't I? Let me see if I wrote notes on it or anything. So… For the physiological pH, it would be 7.4, correct? Is that what you're using that number okay Yes. So, yeah. So it's I guess it's the neurons on this side and the plasmas on the other side. Which side is going to have more Let's see which side of the blood brain barrier will experience a greater fraction of drug ion trapped the plasma or the neuron. So it's a weak acid. With a pKa of nine. So if you so if you Think about your whole scale. And the PK is about here. At your 50% mark. If you were to put it in any solution. You know to the left of that a greater fraction would be non-ionized, right? So you're 7.2 and you're 7.4. Are going to be both on that side. So I said, which will experience a greater fraction of drug our ion. Trapped? Would it be the 7.2 or the 7.4? What did I say the answer was? Why is it the plasma? Can anybody explain? The plasma. Why the plasma? I can give it a shot. Okay. So your equation is HA, which is the unionized formed And then your H plus plus your A minus, that's your ionized form. So if you look at your scale as you approach the 7.2, you're going to be more in your unionized form. And it will remain… dual cross plasma. The blood-brain barrier. However, at 7.4, you're on your H plus ionized So being in the plasma is more ionized. That's my understanding from it. Yeah, I mean, so basically, and it's very close, right? I was a little tricky on this one. 7.2 and 7.4 is going to be very, very similar. But your 7.4 is just ever so slightly basic compared to 7.2. So you would expect more base on the plasma side to take place hydrogen away from your acid. And so you're going to probably have just a slight increased fraction of A minus floating around. On this side of the membrane versus this side of the membrane. Don't get too deep into the weeds of it being trapped or not trapped. This was really me trying to figure out a different way to ask you the same basic ionization type of problem to word it a little bit differently to get you to think about it. But that's really all it is, is that this pH is a little bit higher And it favors more the side going towards a higher concentration of conjugate base, which is a minus floating around. Does that make sense?