I'm here today to discuss a brief synopsis of the pharmacology we use for general anesthesia. While it's not an all-encompassing lecture of the pharmacology that's required for every general anesthetic, and it's certainly not inclusive of the many pharmacologic agents we use in our nurse anesthesia careers, it is a humble beginning for you to acquaint yourself and dip your toes in the waters of anesthesia pharmacology. I'm Sarah Jerome. I'm the program director at the Kaiser Permanente School of Anesthesia, and I've been practicing anesthesia and educating CRNAs for close to 20 years. Before I begin any lecture, I do like to go over any conflicts of interest and some disclosures, and I'm here to say that I have no financial relationships or affiliations with any organizations that could be perceived as a conflict of interest concerning the content of this presentation. The lecture was self-funded. I received no compensation from any external entities that might benefit from the information being discussed in this presentation today. The content of the lecture is based on rigorous academic and scholarly work that I've done. All data, sources, references used in today's lecture are all sourced from credible academic publications with verified data. Any opinions expressed are my own and are grounded in the existing body of knowledge in the field of anesthesia. I've been a CRNA educator and clinician since 2005, with notable publications in pain, nursing and nurse anesthesia texts, journals. I have a BS in biochemistry and cellular biology from UC San Diego. I received my BSN and my master's in nurse anesthesia at Columbia University in New York City. I have a PhD in nursing from the University of San Diego, and I was a recipient of a doctoral research fellowship and research grant from the American Association of Nurse Anesthesiology Foundation. I also have NIH-funded research that focused on neuroimmune inflammation in chronic pain patients. I now primarily focus on SRNA and CRNA research endeavors, but I have been involved in many different types of studies, including the Phase III studies on Sugamidex. I've served on the California Association of Nurse Anesthesiology Board of Directors and I was elected in 2021 to the NBCRNA Board of Directors, and I continue to champion that CRNA credential. As an educator, advocate, researcher, I have presented at a number of different state and national conferences. I've certainly spoken at graduations and hospital grand rounds. I've interviewed on podcasts, and I was named a fellow of the AANA in 2021. I'm thrilled to be here today. Today's course objectives include identifying the pharmacologic agents that we commonly utilize in our general anesthetics. We're going to talk about the main classes of anesthetic agents, including inhalational anesthetics, intravenous anesthetics, and adjuvants. We also want to discuss the mechanisms of action, the pharmacokinetics, and pharmacokinetics is a fancy term for what the body does with the drugs once the drugs are administered. That includes things like metabolism and clearance. In addition to the pharmacokinetics, we're going to talk about the pharmacodynamics of these agents, and the pharmacodynamics, everyone, that's just what the drugs do to the body, the side effects, things you can expect when you administer the drugs. We'll analyze potential side effects and complications such as respiratory depression, cardiovascular instability, and malignant hyperthermia. Our second course objective is to explore the clinical application of the pharmacotherapeutics involved in general anesthetics. I want you guys to be thinking critically and problem solving. I want you to be thinking about managing the pharmacology in a clinical context. To give a synopsis of general anesthesia pharmacology, one should first have a clinical context of the temporal nature or a timeline of how and when CRNAs administer these powerful agents. It should be noted that while I describe a timeline of sorts here for when the agents are administered for general anesthesia, this is just a generic timeline. The timeline is not the only way to administer these drugs, nor is the list of drugs exhaustive. In fact, some clinicians use very different medications and time the administration of those drugs quite differently. Due to the time constraints of this online lecture, let's stick to the basic pharmacologic agents, when we give them, and how they work with one another to result in a patient that is safe and asleep. We typically start in the preoperative holding area before an anesthetic is given. The patients come in for surgery and they're given an anxiolytic or an anti-anxiety medication like a benzodiazepine. This relaxes our patient, right? A lot of patients have anxiety before surgery or procedures. So a drug like midazolam, the other name being Versed for midazolam, that drug is given preoperatively. Patient's nice and relaxed. We bring them to the operating room. And in the operating room, we transfer the patient from a gurney to the operating table. We attach monitors, we pre-oxygenate them, and we start the induction of general anesthesia. The induction of general anesthesia is really the process of rendering the patient asleep. Those drugs that we use for induction are opioids, lidocaine, lidocaine is given because some of our induction agents burn when we administer those through an IV, and then a neuromuscular blocking agent. To keep the patient asleep or to maintain our general anesthetic, we typically give an inhalational agent. And we'll go into those inhalational agents what keep the patient asleep. Those agents are delivered through the lungs and they're administered through a laryngeal mask airway, LMA, or a general endotracheal tube. So let's start with that first class of drugs I talked about that we give in the preoperative holding area. Those are our benzodiazepines. And I said that midazolam, or Berced, is usually the first medication we give to just relax our patients so they don't have as much anxiety when we bring them back to the operating room. I want to highlight just a little bit of history because all of my students know I love history. Benzodiazepines actually came about in the 1930s, but Librium, or the first really clinically utilized benzodiazepine, wasn't really brought about into practice until 1955. And we see it more commonly given and utilized by clinicians in the 1960s. We found that this drug class, benzodiazepines, really had a great anti-anxiety and hypnotic effect. So perfect for taking the edge off right before surgery. Everyone buckle in because we do have a few physiologic receptors to talk about when we discuss anesthesia pharmacology. One of them is the receptor that binds to gamma-immunobutyric acid, GABA for short. GABA is an inhibitory neurotransmitter. It's also an inhibitory physiologic receptor. It slows action potentials down in the central nervous system. So it's no surprise that many of our anesthetics activate this inhibitory pathway. Remember, if we're slowing cognition down, we're making them relax, we're putting the patient to sleep. There's a lot of CNS inhibition that has to occur, and how we make that happen is by activating inhibitory pathways. GABA is the most abundant inhibitory neurotransmitter in the brain. GABA A receptors, pictured here on this slide, represent the most abundant receptor type for this inhibitory signaling molecule. GABA A receptors are broadly distributed in the CNS, so that means they're all throughout the different parts of the central nervous system, and they regulate neuronal excitability. They certainly seem to mediate unconsciousness and certainly seem to help our general anesthetics. The GABA A receptor, which is an ion channel receptor, is activated by the binding of the neurotransmitter GABA. This binding of GABA to GABA A receptors initiates the movement of chloride through the ion channel. Chloride goes into the cell, and this results in the hyperpolarization of the postsynaptic cell. That, in turn, inhibits neuronal cell excitation. Benzodiazepines act on a subset of the GABA A receptor containing gamma subunits. That potentiates chloride conductance once GABA binds to the receptor. The clinical effects of benzodiazepines are a result of basically an agonist action at what are termed the benzodiazepine receptor binding sites on GABA A receptors throughout the CNS. GABA is the major inhibitory neurotransmitter in the CNS, remember, and it's looking for those GABA receptors. The receptor complex, pictured here, is composed of a five-portion or subunit array of protein subunits that contain binding sites for GABA, benzodiazepines, barbiturates, which was an old class of induction anesthetics, ethanol, especially if you go out drinking on a Saturday night, propofol, and many other sedatives. Remember, if you're going out drinking, your cognition is slowing down too, so it's no surprise that the same receptor that's slowing you down after a few drinks is also slowing you down when we give you some anesthetics. The GABA A receptor exerts its effects by modulating, obviously, this chloride channel movement, and many different families of GABA A receptors exist. These subtypes are going to vary by location, their function, pharmacologic effects, but we're really focused on the GABA A receptor and decreasing neuronal transmission, inhibiting CNS cognition and function, putting the patient to sleep, making them nice and relaxed with our benzodiazepine. Because benzodiazepines are working on that GABA receptor and that inhibitory neurotransmitter GABA, the side effects, the pharmacodynamics of this drug class are primarily based in the CNS. We don't see a lot of cardiac or extra CNS side effects. They're not going to work in their cardiac muscle fiber. They're not working in our GI tract because those receptors aren't there. All of the pharmacodynamics, the side effects, things we can expect to see when we administer a drug like midazolam, or things like sedation, anxiolysis, our patients become nice and relaxed, and that's a good thing. Because before surgeries and procedures, our patients are quite nervous sometimes. When we inhibit CNS activity, it's great for preventing seizures. So it's a great anti-convulsant class of drug. These drugs also give some amnesia and they can be considered a hypnotic. So again, our patients are administered midazolam and pre-op to relax them. This provides a little level of fatigue and drowsiness, which is great for starting to put a patient to sleep. And we like Versed in the pre-op area because it burns a lot less than things like diazepam when we inject it through an intravenous catheter. In addition to being a lot less painful on IV injection or when we administer midazolam, we prefer midazolam over agents like diazepam because it is more potent. We do like our drugs strong and we like them to work pretty fast in anesthesia because most of our drugs are administered in a bolus fashion. The pharmacologic effects of benzodiazepines, as with other anesthesia induction drugs, which we will talk about, they're primarily terminated by the redistribution of the drug out of the CNS. Their pharmacokinetics are influenced by a lot of different things, so that's why anesthesia is an art. The pharmacokinetics of this drug class, especially midazolam, as with many of our other drugs, are influenced by the patient's age, their gender, if the patient's obese, and certainly their hepatic and renal status. The pharmacokinetics of the three available intravenous benzodiazepines are pretty similar with a few important differences, one of them being midazolam really exhibits a higher clearance rate than the other two and therefore shorter acting. This is a good thing because we want our patients waking up and not being as sleepy or cognitively impaired at the end of the anesthetic. Both midazolam and diazepam are metabolized by cytochrome P450, which you'll hear a lot about in anesthesia pharmacology. These are enzymes in the liver. It's a family of liver enzymes that usually are subject to interactions with other medications like erythromycin antifungal medications, so we have to be a little bit careful in patients receiving those medications when we administer something like midazolam. Remember, the class of drugs of benzodiazepines are not working to directly open up that GABA-A receptor. They're working to help and enhance the neurotransmitter GABA's basic action on that receptor. So because they're not directly opening up the GABA-A receptors, benzodiazepines have a physiologic ceiling to their side effects, and we think about the ceiling effect as being self-limiting in the CNS because, again, if they're not directly opening up that channel, there's only so much it can do at the receptor. So we see that there is a limit to the amount of CNS depression that can happen if something like midazolam is just given by itself, but as you all know from the ICU, when you combine other drugs with benzodiazepines, that can lead to very dangerous respiratory depression. So even when we preserve the respiratory drive by just administering solely one drug like midazolam, that can increase the likelihood of airway obstruction, and we have to be especially careful if we just give Versa to somebody with obstructive sleep apnea or an elderly patient. So we say that benzodiazepines like midazolam are what are known as synergistic with other CNS depressants, and synergy is really the cooperation of two or more drugs or substances that produce a combined effect that's greater than the sum of their separate effects. You get a lot of bang for your buck when you combine a drug like midazolam with, say, an opioid. So an important and unique feature of benzodiazepines compared to other GABA sedative hypnotics is that we have a competitive antagonist for the reversal of benzodiazepine effects, and as an intravenous rescue agent, that's known as flumazenil. That can rapidly reverse CNS depression, and we can definitely reverse any kind of overdosage of a benzodiazepine administration. The dosing is listed here on this slide for your perusal. After we give a benzodiazepine in the preoperative area, or maybe on our transport back to the OR, we get our patient to the operating room. We'll transfer our patient from the gurney to the operating room table, we'll apply our standard monitors, and we'll start pre-oxygenating our patient in anticipation for induction. Induction is really the reference to the start of anesthesia, when the patient is rendered unconscious, and the IV induction agents that we administer through their IV allows a patient to just drift off to sleep very pleasantly, while us, we're able to rapidly achieve surgical levels of anesthesia. I'll highlight that we're not going to be talking about the barbiturates. Barbiturates are an older class of induction drugs that were introduced in the 1930s, but have been stopped in manufacturing since about 2011 in the US. We still use intravenous push or boluses of these induction drugs that I'm going to describe to initiate our anesthesia. That's pretty much the standard of induction these days, and propofol is that current standard agent rather than barbiturates. We widely use propofol to induce general anesthesia. We also use propofol for IV sedation. We have a few other induction drugs known as etomidate and ketamine. Those are valuable agents, and we can certainly use those for different types of anesthetics where maybe propofol is undesirable, and then we also have a drug called dexmedetomidine, which is also gaining popularity and has some niche uses as well. All of our induction drugs, propofol, etomidate, barbiturates, they also interact with that GABA A receptor, and they're working primarily closer to the beta subunits on that five subunit receptor. Propofol is now the most widely used intravenous anesthesia agent, and while it's primarily used for inducing anesthesia or making the patient asleep and ready for general endotracheal anesthesia, it's also used for procedural or ICU sedation, and it can be used instead of an inhalational agent in what's known as total intravenous anesthesia. That's where a continuous infusion of higher dose propofol keeps the patient asleep for the entirety of their surgical procedure. It was introduced in the late 1980s, and it's listed as an essential medication by the World Health Organization. Propofol is prepared as a white milky solution. It's a 1% solution in a lipid emulsion, and that lipid emulsion is basically some part soybean oil, glycerol, and then also a component of egg, and this unique preparation is unfortunately very favorable to bacterial contamination, so any open vials or syringes should be discarded within six hours if propofol is aspirated or taken out of its original container. Like many other sedatives that we give in anesthesia, propofol appears to exert its effects via the interaction with that gamma-amino butyric acid neurotransmitter and the GABA-A glycoprotein receptor complex. After an intravenous bolus dose of propofol is administered to a patient to induce them for general anesthesia, there's rapid distribution of the drug to the central nervous system and other highly perfused areas of the body that results in a very fast onset. It's generally one circulation time of the patient, and as distribution continues, the drug is circulated to less perfused tissues like the muscle and bone, and what happens is the brain concentration falls. This effect leads to a rapid reawakening of the patient after, say, a sedative or induction dose of propofol. The time of awakening of a patient is dependent on the amount of propofol we've given, or the dose, and also different patient factors, so it's considered dose- and patient-dependent, but awakening time from a bolus dose of propofol is usually in the range of about 5 to 15 minutes. Metabolism. Metabolism plays very little in the initial awakening of a patient. Remember, that awakening happens because there's redistribution away from the central nervous system of propofol, but metabolism is important in the eventual clearance of the drug, getting the drug out of the body. Propofol is metabolized in the liver by cytochrome P2C6B6. We also have cytochrome P2C6 enzymes, and in the liver by the UGTHP4 enzymes. The drug's kinetics are also influenced by the patient's age. We see that more elderly patients usually require a lower dose of propofol to get them ready to be induced for general anesthesia. Speaking to the pharmacodynamics, or the physiologic effects of propofol, it matters how much propofol we're giving and how fast we're giving this drug. If we're giving propofol as an induction agent, a bolus dose to get the patient quickly off to sleep, what we're going to see is a rapid loss of consciousness, and that patient is going to pretty much rapidly emerge from that anesthesia in about 5 to 15 minutes. This is part of the CNS, or neuro effects, of this drug. If we want to keep a patient nice and sedate, but they're breathing on their own, and they're nice and relaxed, we'll use a low dose infusion. This is also sedation, anxiolysis. These are also side effects of this drug when given as a low dose infusion. We do this for monitored anesthesia care cases, where we want the patient breathing on their own, but they're sedate, they have no anxiety, they also are afforded some amnesia with low dose infusions. So, a great type of anesthetic to do probably less invasive anesthetic cases, where the surgery isn't as invasive. Propofol is also very neuroprotective, and what I mean by neuroprotective is it's great for neuroanesthesia cases. Propofol itself is a cerebral vasoconstrictor, and that's good in patients that have really high ICP, or intracranial pressure, because by vasoconstricting the vessels in the brain, we're going to lower the cerebral blood flow, we're going to lower the ICP, hopefully preventing any further ischemia or damage to the brain. A great property of Propofol. Propofol also has some cardiovascular effects that we have to pay particular attention to and should note, especially when we bolus this dose to get a patient off to sleep. Propofol is going to decrease the blood pressure of patients when we give a big bolus dose to get them unconscious and ready for our endotracheal tube. So, we worry about significant hypotension in those induction doses when we bolus this drug. We usually think about, you know, we predict hypotension in patients that are older, especially patients that have ages greater than 50 years. If the patient's sicker, if the patient, and by that I mean if the patient has an ASA classification of 3 or 4, ASA is the American Society of Anesthesiologists classification system. If the patient has a very low blood pressure to begin with, right? If we bolus a huge dose of propofol to get them off to sleep, that already baseline blood pressure is gonna fall quite a bit more. And then of course we worry about synergy. Remember, if a patient's been co-administered a very high dose opioid like fentanyl, if we bolus a huge dose of propofol, you better believe that we're gonna see some hypotension in that patient. We also see respiratory depression with propofol. It's no surprise that if we bolus an induction dose of propofol, the patient is going to not only lose consciousness very rapidly, they're also gonna stop breathing. And that's a good thing. In anesthesia, we don't want the patient moving. We wanna have a nice still airway so that we can do our direct laryngoscopy and place our endotracheal tube. Causes way less damage. It's a much safer way to place an endotracheal tube without the patient moving or breathing. So that's one of the reasons we actually like respiratory depression with this drug in that dosage. We see a lot more respiratory depression with propofol when we give it as opposed to other drugs like etomidate or ketamine. We'll talk about those induction drugs in just a little bit. If we give propofol as a low dose infusion, okay, again, we're not bolusing a lot in a really quick manner. If we give a low dose infusion, we see that patient's tidal volumes come down, but their respiratory rate really generally isn't affected. So again, it matters how much we're giving and the speed in which we're giving it. Again, apnea can happen when you give a big dose really quickly, but for MAC cases, monitored anesthesia care, the patient can stay breathing the whole time, be sedate, have amnesia, be relaxed. It's a great, very versatile drug. So keep in mind, it matters how much you're giving and it matters how you're giving it. Propofol also has some bronchodilating effects. As we're gonna learn in future slides, propofol or ketamine are the preferred induction agents for patients who have asthma. I want to just bring up that it is a little bit specific to propofol in that we have to be particular about the types of patients we give it to, especially when it comes to allergies. I said that this drug is prepared in a lipid emulsion that has eggs and soy. So we want to be very careful about who we give this type of drug to and the preparation. Different manufacturers manufacture propofol differently. So pay attention to your package insert. We typically avoid propofol in sulfite-sensitive patients. And if they've ever had an allergic reaction to propofol in the past, let's steer clear of propofol, all right? So again, in egg or soy allergy patients, we just have to pay particular attention to the preparation, the formulation, or which company has manufactured it. Read the package insert and always talk to your pharmacist in the OR just to be extra special careful in these patients. So it should be no surprise that propofol is an extremely versatile drug. We use it to induce general anesthesia before we instrument the airway. We can use it as a higher infusion dose to completely offset or augment our inhalational agent. We can use it in lower dose infusions for MAC anesthetic cases. So the patient's amnestic, they have nice anxiolysis, they're sedate, they're comfortable for their procedure. So lots of different ways we can use this drug. And it has to do, again, with how much we're giving and how fast we're giving it. Propofol, great for anti-emesis. So if we want to produce a patient that doesn't have a lot of nausea and vomiting, propofol infusions are great to run during general anesthesia cases. They're also great as an antipyretic. So it will decrease the effects of opioid-induced itching. So anti-itch drug, also great as an anticonvulsant. Lots of different ways we can use propofol. The dosing's listed here. To induce a patient, we want to get them off to sleep fast. We give two to two and a half milligrams per kilo. That's gonna get the patient asleep in about 30 seconds. And again, in about five to 15 minutes, that patient will start waking up. So we have to get our airway in and get the gas on if we are going to keep that patient asleep. If we're doing a MAC anesthetic, I list the dose as an infusion right here on this slide. If we want to continually produce anesthesia as a total IV anesthetic without any inhalational agent, we would run a much higher dose of propofol continuously throughout a case. And unlike our narcotics, our opioids, benzodiazepines, we don't have an antagonist or a reversal for propofol. The next induction drug I'll discuss is etomidate. Etomidate's current clinical niche is an alternative to propofol to induce general anesthesia with fewer cardiorespiratory effects. The mechanism of action of etomidate, like many other CNS depressants that we've discussed, involves, you guessed it, the GABA receptor in the central nervous system. There is rapid redistribution of etomidate that accounts for its extremely short duration of action. Shortly after an intravenous bolus injection, usually within a minute, the brain concentration of etomidate rapidly rises. And then, because the drug is so lipid-soluble, over the next several minutes, there's this extensive redistribution out of the central nervous system to other organs and tissues. Then the patient regains consciousness. Etomidate is rapidly metabolized in the liver by hepatic enzymes and plasma esterases. Ester hydrolysis is the primary mode of metabolism in the liver and the plasma of etomidate. The primary clinical advantage of using etomidate over propofol to induce general anesthesia is the hemodynamic stability the patient is going to exhibit upon induction. However, in patients with compensated heart disease, changes in the heart rate, the pulmonary artery pressure, cardiac index, SVR, or systemic vascular resistance, and the systemic blood pressure usually aren't as significant as with induction with propofol. No significant cardiac dysrhythmias are associated when you administer etomidate. So we really value the hemodynamic stability of this induction drug when we have patients with sick hearts. The hemodynamic stability with etomidate is attributed primarily to a unique lack of depression of sympathetic nervous system functions and baroreceptor function. In addition to being a more hemodynamically stable induction drug or having a more hemodynamic stable side effect profile compared to propofol, etomidate does have side effects similar to propofol. Patients will indicate that when you bolus etomidate for induction of general anesthesia, it is painful. All right, patients might jerk or have abnormal muscle movement, that's myoclonia. And literature, the data all indicate that you run the risk of a higher incidence of postoperative nausea and vomiting when you use etomidate for your induction drug. That's especially the case when you also combine that with the use of opioids intraoperatively. So etomidate has been associated with that kind of negative disadvantage as an induction drug. The other negative disadvantage or side effect we're particularly concerned about with etomidate is adrenal cortical suppression. Etomidate inhibits the enzyme 11-beta-hydroxylase, which is essential in the production of corticosteroids and mineral corticoids. So even with just a single dose, there is research and literature out there that shows a clinically significant reduction in steroid production in patients who receive etomidate. So we have to be particularly careful in any patient that might be steroid deficient or have a difficulty in producing steroids. We don't wanna put a patient into adrenal cortical suppression just by our induction agent. The porphyrias are also a group of patients that have a rare metabolic condition that is caused by deficiencies in the enzymes that are involved with the biosynthesis of heme, heme being a building block of hemoglobin. Any drug that induces this enzyme has to be avoided. So we don't like to give porphyria patients etomidate either. So just be careful that there are patients with known sensitivities, certainly if they're already in adrenal suppression or if they have an acute porphyria condition, we don't wanna give etomidate to those patients. I've listed the induction dose of etomidate here to induce general anesthesia. And I want to also highlight that there is no antagonist for this induction drug. If you give too much etomidate, you can't reverse it. There is no reversal blocker or antagonist that you can give to reverse an overzealous administration of this induction drug. Ketamine is the next induction agent we're going to discuss. It was clinically made available in 1970, but it is an analog or a cousin of PCP, which was used in psychology, had a lot of psychedelic references in the 50s and 60s. It is in that same class as PCP. Now, ketamine being a derivative, a cousin of PCP, has a lot of interesting psychic side effects too, which we'll discuss. It has a lot of pharmacologic effects that differ very greatly from our classic anesthetic induction drugs. And it also renders a very unique anesthetic state, which we'll discuss. Be careful with ketamine because there are many different clinical preparations. It comes in various different formulations. So please be careful with the dosing. Also know that the preservative that it's manufactured in and prepared with, many formulations have a neurotoxic preservative. So we never ever give ketamine through a spinal or epidural. Ketamine is different because guess what? It's working on a different receptor. Ketamine is blocking or causing antagonism of the N-methyl-D-aspartate amino acid receptor in the brain. N-methyl-D-aspartate is NMDA receptors. So this drug is actually blocking, antagonizing an excitatory receptor. This is why we have a little bit different of a side effect profile here. So ketamine blocks NMDA receptors in the brain, and that results in a very selective depressant effect on different parts of the thalamus, most notably the medial thalamic nuclei that are very much responsible for blocking signals of pain perception as they travel from the thalamus to the cortex. So we see that ketamine is a great analgesic, okay? The anesthetic state that ketamine elicits is unique because it doesn't encompass the usual signs and stages of anesthesia that we typically think about with our CNS depressant induction agents. It actually produces a catatonic state where the patient is gonna feel or report being feeling separated from their environment. They have a profound analgesic sensation, and they also get some amnesia from this drug. But what's interesting is with that analgesic and that kind of separation feeling, they still retain their protective reflexes of their airway. It's also a cardiac stimulant, which we're gonna discuss. So ketamine-induced anesthesia states are coined dissociative anesthesia. That's a concept that Corson and Domino introduced. But this dissociative state is very, very different from our other CNS induction drugs. And similar to propofol and etomidate, ketamine has no reversal agent. There is no antagonist for ketamine. So be very careful when dosing your ketamine because you can't reverse it. Some of the more notable pharmacodynamics of ketamine obviously are gonna involve the central nervous system because our NMDA receptors that ketamine is working to block obviously play in the CNS. So we get these odd CNS effects, different psychic disturbances. Primarily, we're giving ketamine for that dissociative state to render the patient unconscious. Now, patients are gonna have a lot of odd side effects, one of them being nystagmus. That's pictured here on this slide. You see the eye movement rapidly moving back and forth as such. That's nystagmus. So patients might not actually close their eyes on induction. Their eyes might stay open and you might notice this particular side effect with ketamine induction. Ketamine also has been noted to raise intracranial pressure and cerebral blood flow. So we don't use ketamine typically in our neuroanesthesia cases because again, if a patient already has an abnormally high ICP, we don't wanna cause any further damage or ischemia to that poor brain that's already working under very, very difficult conditions. Now, we also see very odd emergence reactions. When the patient is coming back or returning to consciousness after being induced from ketamine, there's these emergence reactions that are a result of visual, auditory, proprioceptive, different types of hallucinations. And patients describe this phenomenon as like illusions, sensations of drunkenness, altered states of consciousness, restlessness, and also combativeness. So we typically will administer a benzodiazepine like midazolam to significantly decrease the incidence of these reactions. Patients who are administered ketamine will also have excessive secretions like tearing, salivation, it can actually be very profound, drooling. So we like to give a drug like an antipsychologic like glycopyrrolate to dry up these secretions. So we're giving a benzo for those psychic disturbances. We also have to give something to dry up all these secretions. But we see increased muscle tone, certainly that nice stagnant in the muscles of the eye, moving it back and forth, random movements in the body. Respiratory-wise, ketamine is a great drug because spontaneous ventilation in these patients is generally very well preserved. That's great to maintain normal respirations when you don't want the patient to become apneic. If you give a large enough dose of ketamine and you give it in a bolus fashion very rapidly, you can see transient apnea. However, this drug makes it very safe to do say burn dressing changes. I was a burn ICU nurse. We used to give ketamine so that the patients wouldn't need to be intubated for these burn dressing changes. Great analgesic properties, but the patient still breathes on their own. Arterial blood gases remain where the normal limits and the central response to carbon dioxide is maintained so patients are gonna continue to breathe. Ketamine's also great for any kind of bronchospasmic patient like asthmatics. Ketamine increases pulmonary compliance, it decreases pulmonary resistance, so it's a great bronchodilating induction agent. So we consider it one of the best drugs to give our asthmatics in addition to propofol. Ketamine, unlike our other IV anesthetics, also act as a circulatory stimulant. It produces increases in blood pressure, heart rate, cardiac contractility, and cardiac output, as well as central venous pressure. That's fantastic for patients where their blood pressure's falling, their heart rate is falling, right? We get these positive inotropic effects from ketamine being a very, very great advantage to using this induction drug in cases where the patient might have a very low volume status. They're hypovolemic, they're in shock, maybe they're a trauma patient. So again, any patient who's hemodynamically compromised because of shock, trauma, debilitation, hypovolemia, it's a great drug to maintain hemodynamic stability and not totally make them hypotensive and crash on induction. Getting to the pharmacokinetics of ketamine, like our other induction drugs, when we just give a single bolus dose of ketamine, brain concentrations decrease rapidly as the ketamine is redistributed from the central nervous system compartment to the periphery and the redistribution accounts for the termination of the drug effect and return to consciousness. So we see that ketamine has a very high clearance rate, which means it has a very short elimination halftime. Metabolism for greater than just single doses, when you give lots of ketamine for repeated burn dressing changes or you have to give it continuously during a case, is metabolized by hepatic microsomal enzymes. That's responsible for the biotransformation or metabolism of ketamine. And the primary pathway for ketamine metabolism is the cytochrome P450 system. I've listed the dosing of ketamine. You can give ketamine both IV or intramuscularly. That will produce an anesthetic state in about three to five minutes. And again, rapid redistribution is the primary way this drug stops working or the patient starts to become more conscious. That typically happens after a single dose in about 15 minutes to about a half hour. Again, we use ketamine for sedation, general anesthesia, in TIVA cases. We can use it for a lot of different types of surgical or procedures that we're involved in. It's great for induction of anesthesia in high-risk patients, those patients who might have shock, cardiovascular instability, patients who are hypovolemic, trauma, if they have bronchospasm and are asthmatics. So again, great drug when used appropriately in the correct patient population. So ketamine, it's a great induction drug, has a lot of versatile uses, certainly a very potent analgesic, and a lot of patient populations that benefit from the use of inducing general anesthesia with. However, there are clinical caveats, meaning we do have to consider all of those secretions. We gotta dry up the secretions, so we have to give something to dry those up. Also, those psychic, hallucinatory side effects, we obviously need to give a benzodiazepine to hopefully prevent those bad side effects. But there are also patient populations that we really should be very cautious in administering ketamine to. And those patient populations that require caution are patients with very, very acute high hypertension, very high elevated blood pressure levels, which might precipitate other clinical signs of badness, like rupturing and aneurysm or such. Be careful with giving ketamine to those patients. Patients with angina, all right? If we increase the myocardial contractility with ketamine, we need to be careful of patients with a preexisting condition of angina. CHF patients, patients with high intracranial pressure or intracranial hypertension patients. We don't wanna cause any further ischemia or damage to the brain. Patients with increased intraocular pressure. Again, if the eye is moving back and forth with that nystagmus and the muscles are tensing up, we really don't want to cause any more pressure on the intraocular contents. And of course, any patient with psychiatric disease or existing psychiatric disturbances, we wouldn't wanna precipitate any further psychiatric side effects by administering ketamine to those patients. Now we're on to opioids. This is our next class of drugs that we use in general anesthesia. And we do give some opioids on induction of general anesthesia. I wanna just highlight though, in clinical practice, opioids are used to relieve pain during a number of different cases as well as during general anesthesia. The inclusion or a clinician's inclusion of opioids is usually to reduce pain and anxiety of the patient. It decreases somatic and autonomic responses to when we instrument the airway and we place our endotracheal tube. They can lower the requirement for the amount of inhaled anesthetic agent. And obviously we need opioids for postoperative analgesia in a lot of different surgical cases. I will touch on the fact that because of the societal opioid epidemic that we're facing in America, clinicians are exploring the practicality of providing opioid sparing or opioid-free techniques in anesthesia. So these approaches really attempt to minimize, they attempt to eliminate the short and long-term adverse effects of opioids when we use them perioperatively. And really, the potential benefits to opioid sparing and opioid-free anesthesia include shorter discharge times, fewer unplanned hospital admissions, significant decreases in opioid use in the post-anesthesia care unit or PACU, and the strategies to lower the opioid use include all different kinds of non-opioid adjuncts, so using IV lidocaine, using ketamine for analgesia, using IV NSAIDs, different types of steroid combinations or multimodal analgesic techniques, in addition to regional techniques where you numb a portion of the body, or perhaps use like a spinal or epidural to control pain for the procedure, just so we don't have to use as many opioids. I will say that there is a huge variation in dosing of opioids in anesthesia depending on the type of patient, their history, and the surgical situation. This is going to lead to vastly different durations of action, even with the same drug. For instance, fentanyl can last anywhere from 30 minutes to 24 hours depending how it's administered and how much is actually given. The pharmacokinetic parameters are important in the class of opioids, but the clinical context of how these drugs are used in clinical practice is really the major factor in how the patient's going to respond to these drugs. Pharmacodynamics and pharmacokinetic considerations have to be combined to reach the ideal analgesic for general anesthesia. So what I mean by that is that it's an art. Anesthesia is an art and we have to combine all of this to make a great analgesic clinical experience for the patient. Surgical requirements for these analgesic drugs are going to be very different from say non-operative uses. If you're doing a procedure like a colonoscopy, it's going to be very different from if you do something with a surgical incision. Huge, right? So the differences include much higher analgesic requirements for surgeries. We're co-administering potent anesthetics during general anesthesia, including sedative drugs. Remember, there's synergy, so we've got to be careful with that. And then there's the ability to support the respiratory effort of the patient, right? We can give a higher dose of opioid knowing that it is going to make the patient apneic because we can intubate the patient and control their ventilation with our anesthesia machine. So there's a lot of different clinical context nuances we have to take into account when we talk about opioids. When small doses of opioids are used, the effects are usually terminated by redistribution out of the actual opioid receptor area to, you know, peripheral places. So redistribution is usually the key to terminating the effects of these drugs rather than metabolism. If we give larger doses, if we use an infusion of opioids or multiple doses of opioids, then these drugs are much more dependent on the metabolism of the patient for the offset of the side effects. Pictured on this slide, I wanted to show you just one type of opioid receptor and opioid receptors. Makes it nice and easy. The opioid receptor is where these opioids are working. I've pictured here the mu opioid receptor. There's many types of opioid receptors, but the mu opioid receptor is pictured on the slide, and this is just one way opioids decrease the pathway of painful sensations or provides analgesia. In this example, the mu opioid receptor not only decreases presynaptic release of neurotransmitter, this is done via those calcium presynaptic channels you see there, but postsynaptically, that postsynaptic neuron, that opioid receptor there is going to hyperpolarize that cell so it can't fire. With no neurotransmitter released, the sensation of pain can't be relayed, and even if some neurotransmitter is actually released and reaches that postsynaptic neuron, that postsynaptic neuron is going to be hyperpolarized and unable to carry the message of pain further on down the road. You know I'm going to weave in just a little history here, everybody, and opioids are a great class of drug to talk about history because we have a really long history of using opioids in the human species. In fact, one of the earliest uses of opium is found in Greek literature dating from 300 BC, so this is a very old class of drugs and we've known about the analgesic relaxing effects of opioids for quite some time. Opioid is a term that's used to refer to a group of drugs, both naturally occurring, synthetically produced, that possess opium or morphine-like properties. Opioids really exert their effects by mimicking naturally occurring endogenous, meaning inside of you, opioid peptides, or endorphins, right? Endorphins naturally occur in your body and they prevent your body from feeling pain. That's why you can hear on the news how people rush into burning buildings to save babies and they come out, you know, 80% covered in burns. Their endorphins have kicked in and a lot of those people report that they feel no pain and they just had to go in and get that child. The term narcotic is actually derived from the Greek word narkotikos, which means be numbing, and it really refers to the potent morphine- like analgesics that have the ability to produce stupor, insensibility, and sadly dependence. We see in the 1800s, Sertuner reported the isolation of a pure substance from opium that he named morphine, after Morpheus, the Greek god of dreams. Other opium-derived agents were discovered in 1832, that was codeine. I also list here those agents that are naturally occurring, that's morphine and codeine. We have semi-synthetic opioids, which are things like dilaudid and hydromorphone, and then those that are fully made in a lab, and those are fentanyl, sufentanyl, remifentanyl, those things. And again, those were derived in the lab to address surgery becoming faster, so we need a quick-on, quick-off kind of opioid. Obviously, higher potency, right? If we do a procedure that goes from the occiput all the way down to the sacrum and open up the whole entire spine, you're going to need something really potent to fight off that kind of level of pain. So we see lots of different reasons for different pharmaceutical companies creating more potent and different duration-action opioids. Opiate analgesia results from actions in the central nervous system, the spinal cord, and the peripheral sites. So these opioid agents are binding to opioid receptors in a number of different places, both centrally and peripherally. And typically, opiate analgesia is most effective for visceral pain. I'm going to compare a lot of opiates to morphine. Morphine is the prototype opioid that pretty much all opioids are compared to. So in general, I'm going to give you the side effects and kind of what works best for different types of pain. But keep in mind that at really high doses, many of these agents can relieve a lot of different types of pain and levels of pain. Opiates are not anesthetics. They don't render the patient amnestic. They don't render them unconscious. So awareness under anesthesia is definitely a concern when you're doing a high-dose opiate anesthetic. Opiates in general, but I will refer to morphine here, produce a couple different very similar side effects. And those are rash, itching, sometimes a feeling of warmth in the face or the upper chest and arms. And this can happen both from histamine and non-histamine-releasing opioids. It's especially prominent when we give an opioid through a spinal or epidural. When small doses of opioids are used, the effects are usually terminated by the redistribution of that opioid away from the opioid receptor rather than actual physical metabolism of the drug. When we start giving larger doses, multiple doses, continuous infusions, those are much more dependent on the patient actually metabolizing the drug so that the drug stops working. Like most drugs, opioids are usually metabolized in the liver and the opioid drugs are metabolized by the usual cytochrome enzymes, including cytochrome P3A4, these get hard to say after so long, cytochrome P2D6 and cytochrome P2B6 with the exception of remifentanil. We'll talk about remifentanil because it does get metabolized very differently from any of these others. Opioids and their metabolites are excreted primarily by the kidneys and secondarily by the biliary system and GI tract. One thing of note though, we can see here I've listed morphine specific onsets, the dosing, et cetera, as well as the different preparations. You can see you can administer it in a lot of different ways. However, morphine does have an active metabolite, M6G. So morphine appears to actually produce a more prolonged effect, right? It has a very long duration of action and it's also usually seen with excessive sedation, especially in patients with renal failure. If a patient can't really excrete this active metabolite, we see these prolonged actions in morphine. So definitely be careful in elderly patients or those with decreased renal or hepatic function. Morphine, like most of our other opioids, can be reversed. We do have an antagonist or an opioid blocker and that is nalaxone or Narcan. I have some administration tips here for you as well as some clinical signs to look for when you administer the reversal of opioids. We typically don't try to reverse our opioid analgesia because in anesthesia we're giving it hopefully to prevent post-operative pain. All opioids induce some degree of dose-dependent peripheral vasodilation. What does that mean? With anything that's dose-dependent, we're talking about the more you give, the more of the side effect you're going to see. So all opioids, they produce or induce some sort of peripheral vasodilation depending on how much opioid you administer. And morphine being the prototype opioid certainly has this side effect profile. Much of the hypotension produced by morphine, codeine, and meparidine, that's Demerol, is attributed to histamine release. There are other opioids that don't have histamine release, but they do sometimes affect the blood pressure as well. Those opioids that are absent of histamine release include fentanyl, sufentanyl, alfentanyl, and remifentanyl. Bradycardia results usually from vagal stimulation in the medulla. Myocardial contractility, baroreceptor function, and autonomic responsiveness are usually not affected when you administer opioids. Opiate anesthesia is often used in those patients that are cardiovascularly compromised or challenged because opiates are so much safer and have minimal depression of the cardiovascular system. All opiate agonists usually produce dose-dependent depressions of respirations. We all know that from our ICU days. If we administer an opioid and we give a little too much, we start seeing respirations and spontaneous ventilation slowing down. When we see a dose-dependent respiration decrease from administration of an opioid, that's usually because of the effects on mu and delta opioid receptors in the respiratory centers in the brain stem. Of note, respiratory effects are usually noted with that classic narcotized patient. You all recognize that they're taking slow, deep breaths. Obviously, as you increase the opioid dose further, those slow, deep breaths pretty much cease until we get to a complete apneic event. We're not going for that effect. Opioids have no major effect on nerve conduction at the neuromuscular junction or at the skeletal muscle membrane. Things to note as well, they decrease gastric motility and intestinal activity, prolonging the gastric emptying time, as well as they also reduce the secretory activity in the GI system, which usually we're all well aware of that side effect of constipation in our patients that have been on opioids for considerable time. Postoperative ileus is also something that we have to be concerned of if we administer a lot of opioids to patients. Meiosis or pinpoint pupils is also a very prominent feature of a patient that's been over-narcotized or has been administered a lot of opioids. It is actually still present under general anesthesia. Keep in mind that this is something that some clinicians will check on a patient. They will check their pupils to see how much opioid is on board because we can gauge, depending on the size of the pupil, how much opioid has been administered. There is also an emetic effect. Emetic meaning causing nausea, vomiting. The emetic effect of opioids is kind of a complex issue. We know that patients who receive opioids can have nausea and vomiting because these drugs stimulate the chemoreceptor trigger zone in the area postrema of the medulla. Again, the medulla is a site of action that a lot of opioid receptors affect change and physiologic changes in. Opioids do have an antidiuretic effect. They can decrease the tone of the bladder detrusor muscle and constrict the urinary sphincter, which usually results in urinary retention. Urinary retention is a common side effect, primarily with intrathecal, those being like spinal and or epidural opioid administration. So lots of different side effects with our opioids. And again, because morphine is our prototype opioid, we see the major side effects of this drug class listed here. Let's turn now to hydromorphone or Dilaudid. Dilaudid is derived from morphine. It was made clinically available in the 1920s, and it has a pharmacokinetic profile very similar to that of morphine. That's why morphine is our prototype opioid that we compare all of these other agents to. Dilaudid, however, is much more potent, and we can tell it's more potent because we're giving 0.2 to 0.5 milligrams as opposed to whole milligram aliquots if we administer this drug intravenously. Because of its lipid solubility, it's actually used quite a bit in spinal and epidural administrations, especially when we need coverage for wide areas of the body, when we need more analgesia and we need to cover a greater surgical area. Dilaudid doesn't have any known active metabolites. So unlike morphine, it's usually recommended for patients in renal failure because you don't have that buildup of an active metabolite causing further sedation and side effects. The next opioid we're going to discuss is Meparidine or Demerol. Meparidine works on the Mu and Kappa opioid receptors. It's structurally very similar to Atropine, the anticholinergic. After metabolism by the liver, Meparidine is partially metabolized to an active metabolite known as normoperidine, which is analgesic in and of itself. It is an analgesic active metabolite, but this metabolite also lowers the seizure threshold and can induce central nervous system excitability. In any circumstance where there is an accumulation of normoperidine, that active metabolite, those patients can experience central nervous system excitation and that can range from anything from tremors, muscle twitches, all the way up to seizures. So due to the accumulation of normoperidine, Meparidine's active metabolite, the limitations on Demerol's use should be considered in patients with renal failure, in elderly patients who don't have as high of renal function as they once did. There's different types of patients that we steer clear of using Meparidine in. Meparidine is effective in reducing shivering from diverse causes, including surgery. Many patients, not all, but some do come out of surgery shivering. So whether that be general or epidural anesthesia, Demerol is a great drug to get rid of that shivering. So because of the Kappa receptor stimulation that Meparidine seems to have, the Kappa opioid receptor stimulation or agonism, Meparidine reduces and eliminates visual shivering as well as the accompanying increase in oxygen consumption. You can imagine that there's quite a bit of oxygen consumption happening with all of those muscles shaking. Obviously that's not a great side effect of general and epidural anesthesia. So we want to get rid of that shivering, warm up the patient, we administer, you can see the dosing here, just small amounts of Demerol to just ease that shivering. So of note, we don't really typically use Demerol intraoperatively just because there are safer, more convenient opioids at our disposal that don't have these active metabolites that we have to worry about accumulating and causing seizures. However, great drug for decreasing our shivering in the post-operative area. Fentanyl is the next opioid we're going to discuss, and it is the most widely used opioid analgesic in anesthesia. A single administered dose of fentanyl has a very short duration of action. We typically think about 30 minutes to 60 minutes or a half hour to an hour. And again, it produces a very profound dose-dependent analgesia. It will contribute to ventilatory depression, especially when combined with benzodiazepines. Remember that synergy we're worried about. And of course, sedation. It does decrease propofol dose requirements and certainly helps with our inhalational agents, keep the patient nice and stable. Now, the action of a single dose of fentanyl is typically terminated by that drug redistributing away from that opioid receptor. When fentanyl is given in multiple doses, large doses, or continuous infusion, the termination of fentanyl really reflects more the elimination of the drug rather than redistribution. Of note, fentanyl elimination is prolonged in the elderly and the neonate. Because it's cleared by the kidneys, we have to pay particular attention to those patients where their kidney function might not be as strong as a healthy, normal adult. So keep that in mind. It has many different preparations and availabilities, lots of uses for it, and obviously a very potent analgesic drug that we use quite a bit in anesthesia. Next, we're going to take a look at sufentanyl and remifentanyl. Sufentanyl is the most potent opioid that we use in situations and cases where we need a lot of analgesia, such as in cardiac cases where sternotomy is performed by our surgical colleagues, large spine cases, again, where the whole spine might be opened and instrumented, rods and pins are put in. Usually, patients who receive sufentanyl are in-hospital patients requiring very significant amounts of analgesia and, obviously, post-operative care. This would not be the type of really potent opioid we'd want to administer to a patient who's going home after an outpatient surgery. Sufentanyl is a mu-agonist. It produces, obviously, effective analgesia both intravenously and also in spinal and epidural preparations. It is a highly lipophilic and potent agent, and it has a very short elimination half-life. It's shorter than fentanyl. We have hepatic clearance of sufentanyl, and we also have minimal amounts of the drug being excreted, unchanged, in the urine. The effects of age. We have to be cognizant of our geriatric patient population. We want to be particularly careful in our older patients because of the distribution and elimination of sufentanyl. We see that there is a decrease in the initial volume of distribution in our elderly patients, and this reduced volume of distribution of sufentanyl when we administer it to the geriatric patient population can be associated with an increased propensity for respiratory depression. Just be careful when you administer sufentanyl to older patients. Remifentanyl is a completely different opioid in many different regards. It was designed to be very quick on and quick off, and so it was designed with an ester group in its structure. It's metabolized by hydrolysis in the plasma and tissues by nonspecific esterases, so it does not rely on the liver like our other opioids. It's metabolized by plasma esterases. Remifentanyl has a very low volume of distribution and a very large clearance, which results in a short half-life of about 10 minutes. Due to the potential for respiratory depression and muscle rigidity, bolus dosing of remifentanyl in the preoperative or postoperative unit usually isn't recommended. We use this drug as an infusion during a case, okay? It has a very unique metabolic pathway, short duration of action, and really a precise and rapidly titratable effect because it's very quick on and then it's very quick off. It does have non-cumulative effects. So what does that mean? You are going to have to dose a patient with something more long-acting for postoperative analgesia. Once the infusion or administration of ramyfetanyl is off or completed, you turn it off for the end of the case, that patient's analgesia is going to rapidly diminish. So just so you all are aware, very interesting drug, great for spine cases, neuro cases. Again, you can titrate it with a drip very easily. And once you turn it off, it's rapidly metabolized and it's gone from the patient because of those plasma esterases, very cool stuff. Okay, we're done with opioids and now we're moving on to our neuromuscular blockers. Up until now, we've discussed agents that work on the GABA receptor in the central nervous system like our benzodiazepines and our induction agents like propofol. We've talked about the NMDA receptor that ketamine works on. We've talked about opioid receptors, right? That are exogenous opioids provide analgesic effects to the patient with. And now we're gonna venture out into the periphery of the body to our neuromuscular junction. The neuromuscular junction is the synapse or the intersection of where an alpha motor neuron meets skeletal muscle. And that relays a message of that skeletal muscle to contract. So when my brain says, hey, grab a cup of coffee, Dr. Jerome, my hand can easily do that, all right? When we're talking about initiating a muscle contraction, we're talking about a voluntary movement. We're talking about skeletal muscle. We're not talking about smooth muscle. We're not talking about cardiac muscle, right? You're not actively telling your heart to beat. That's more of an automatic function. So we're talking about voluntary muscle movement and that is what skeletal muscle is. Smooth muscle, cardiac muscle, those are all automated. That's stuff like peristalsis, respiration with your diaphragm, heartbeats, right? We're not actively telling those muscles to move. Skeletal muscle is really responsible for the movement that our surgical colleagues are gonna complain about intraoperatively, right? If they make an incision in the abdomen and have to spread those abdominal muscles apart, if that skeletal muscle is not relaxed, it makes it very difficult to get in there and get the job done. So let's talk about those muscles right now. Skeletal muscle is innervated by large myelinated alpha motor neurons that originate from the ventral or the anterior part of the spinal cord horn and the brainstem. You can see that pictured here as the alpha motor neuron propagates an action potential from the spinal cord, ventral horn or the brainstem, it eventually travels to a skeletal muscle. In order for that alpha motor nerve action potential to be transmitted to a skeletal muscle for a contraction, a few steps have to happen, which are roughly broken down here in this illustration. Keep in mind that the major neurotransmitter in this process is acetylcholine. Acetylcholine traverses the synaptic cleft of the neuromuscular junction and binds to a receptor we haven't yet spoken about, and that receptor is called the nicotinic acetylcholine receptor. When two acetylcholine molecules, those two neurotransmitter molecules bind to an individual nicotinic acetylcholine receptor, the nicotinic acetylcholine receptor opens. If enough voltage-gated receptors open on the muscle fiber, that muscle fiber is going to depolarize and it's this cellular depolarization that manifests as a muscle contraction or muscle movement, muscle twitching. So now we're gonna talk about another class of drugs we use very frequently in general anesthesia, which are our paralytics. They cause skeletal muscle relaxation for general cases, and it should be no surprise that they target these nicotinic acetylcholine receptors. These drugs are known as neuromuscular antagonists or neuromuscular blockers. We use relaxation during induction of anesthesia to give us the best possible conditions for endotracheal intubation and instrumentation of the airway. I guarantee, again, it's way more difficult to get an endotracheal tube in a patient that's moving, fighting you, than one that's asleep and relaxed. So we use paralysis to improve the surgical conditions for our surgeon friend across the drape. Again, many of the surgeries wouldn't be possible today if say abdominal muscles were too tight or the diaphragm was flopping down into their view during a laparoscopic case, or say the patient kicks them when they make incision. It's not a good look. Neuromuscular blockade prevents movement that would otherwise be harmful during a surgery or during a therapeutic or diagnostic procedure. Just think about a patient who needs a cerebral coil embolization in interventional radiology. If that patient sneezed, that obviously wouldn't be a great outcome, I would imagine. So paralysis has its uses, and we're gonna discuss those agents right now. When we talk about neuromuscular blockers or antagonists, this drug class has two subclasses. We have depolarizing agents and non-depolarizing agents, and maybe that's a misnomer. I should say there is just one depolarizing agent, singular, in clinical use, and our depolarizing muscle relaxant, only one, is succinylcholine. Succinylcholines are only depolarizing muscle relaxant that we have clinically available and that we use in anesthesia. It is a very fast-on, fast-off drug, meaning after we administer succinylcholine, the patient is going to be relaxed or paralyzed very quickly, a very rapid onset, usually in less than a minute, and then the drug wears off very quickly. It has a very short duration, so it lasts only about five to 15 minutes in most patients. This drug has a very unique metabolism profile in that the rapid onset and short duration is really due to another enzyme in the blood, plasma cholinesterase, that really very rapidly causes metabolism of this succinylcholine agent and causes it to wear off quite fast. Great drug for when we need rapid intubating conditions. We need the patient very relaxed, very quickly, but also great in circumstances where, say, maybe we don't know how bad the airway is gonna look and we don't know if, by paralyzing the patient, we might not be able to intubate the patient. We use succs so that the patient comes back breathing in five to 15 minutes. We don't paint ourselves into a corner that we can't adequately get ourselves out of. Great drug for rapid sequence inductions when a patient has a full stomach, an unknown airway or a questionable airway where we're very uncertain of what we're gonna find when we take a look with our direct laryngoscopy. Lots of different advantages with this one. Our succinylcholine agent, our depolarizing agent, is unique in that it's structurally very similar to acetylcholine, which is the neurotransmitter at the nicotinic acetylcholine receptor site in the neuromuscular junction. So we have this drug, this pharmacotherapeutic, that was structurally developed to look exactly like two acetylcholine molecules. It attaches to nicotinic acetylcholine receptors, and just as with acetylcholine, what that transmits is that the postsynaptic skeletal muscle twitches, that skeletal muscle is told to twitch or contract. And when you administer SUCCS, what you're going to see is widespread systemic twitching. You're gonna see all of the muscle fibers twitching. Some clinicians say that it looks like mild seizure activity but all of that activity are those skeletal muscles depolarizing, contracting, fasciculating, and then once that stops, the paralysis that is left is because all of that skeletal muscle has depolarized and those cells can't fire anymore. That's why it has such a short duration of action in addition to those very, very effective plasma enzymes. So very quick on, quick off drug that has some very interesting side effects when you administer it. We don't typically use succinylcholine unless it's an emergency in pediatrics. There are also other patient populations we don't use succinylcholine in and it has to do with the neuromuscular junction and in pediatric cases, we're worried about undiagnosed muscular dystrophies. Certainly we don't use succinylcholine in burn patients because of all of the different nicotinic acetylcholine receptors that proliferate when some patients have been bedridden or burned for a very long time. So there's patient populations we have to be very careful that we do not administer succinylcholine to and you'll learn all about that when you get to your anesthesia classes. This drug is dosed on the total body weight of the patient which is different from some of our other drugs that we will discuss. So again, to highlight, we like succinylcholine, our depolarizing muscle relaxant because the patient will resume spontaneous ventilation rather quickly, okay? Great in those cases where we're unsure of the airway, the patient has a full stomach and we need rapid paralysis. So lots of different reasons and you'll learn all about the other reasons we like succinylcholine. Succinylcholine is an old drug and it does have some side effects. So we don't like succinylcholine for myriad reasons. Some of it has to do with cardiac dysrhythmias. Certainly you can imagine if a patient's skeletal muscle is fasciculating and you see all of those muscles twitching, that patient's going to complain of some muscle soreness when they wake up, that's myalgia. So myalgias are definitely indicated by patient populations who are administered succinylcholine after induction doses of propofol. Allergic reactions. Actually, succinylcholine and rocuronium, a drug we're gonna discuss in the next non-depolarizing muscle relaxant class, are the most frequently involved agents in allergic reactions when we compare them to the other types of muscle relaxants we use in the OR. Hyperkalemia, okay? Hyperkalemia, the patient's potassium level is going to increase because guess what's effluxed out of those skeletal muscle cells through those nicotinic acetylcholine receptors? You guessed it, potassium. So when we depolarize those cells and potassium effluxes out of those cells, what we see is a pretty profound level of potassium being increased in our patients. So we have to be careful in any patient where a higher potassium level could be detrimental, right? We don't wanna certainly cause cardiac problems with higher potassium. We have to be careful in those renal patients that maybe haven't been dialyzed for a while and their potassium's creeping up from not being dialyzed. We don't like it because it increases intragastric pressure. So all of the muscle contractions, you know, moving and squeezing that stomach, if we increase any kind of intragastric pressure, what would that do to any stomach contents? We'd be very concerned about it coming up and the patient aspirating, all of those contents going into the lungs, causing pneumonia and other clinical signs of badness. Sucks can also increase intracranial pressure. Not great for those neuro cases that we talked about. Intraocular pressure. Again, with all of the muscles moving, we certainly wouldn't wanna lose any intraocular contents from eye muscles squeezing intraocular contents out of an open globe trauma. And then of course, malignant hyperthermia, which you will learn all about in your anesthesia courses. This is the only muscle relaxant that has the ability to cause malignant hyperthermia. The next subclass of neuromuscular blockers are known as our non-depolarizing muscle relaxants. So all of the drugs I'm going to discuss from here on out in this drug class are different from succinylcholine in that they do not cause that postsynaptic membrane to hyperpolarize or those muscles to twitch. If you administer any of these muscle relaxants, you will not see the fasciculations and the mild seizure-like clonic movements. So these non-depolarizing agents actually, rather than agonizing that nicotinic acetylcholine receptor, these actually block the nicotinic acetylcholine receptor. So only one molecule has to attach to the nicotinic acetylcholine receptor for that receptor to be blocked and thus prevent an action potential propagation, meaning that alpha motor neuron can't tell the muscle to twitch because the receptor is blocked by one of these drugs. Atrocurium is the first non-depolarizing muscle relaxant we're going to discuss. It is a combination of a lot of different stereoisomers and it's very, very protein-bound. It actually is very unstable. If left unrefrigerated, and it undergoes a very interesting means of metabolism, Hoffman elimination. Hoffman elimination is shown here on the slide. And Hoffman elimination in just layman's terms is when an acidic solution, so the drug is prepared as an acidic solution in a vial, when we inject that into a human, which is more basic and the temperature is higher than say room temperature, that change in temperature and the change in pH is what causes that drug to degrade. Very interesting type of metabolism. It can also undergo ester hydrolysis, also shown on this slide, but it has an active metabolite and that is something we have to be cognizant of, especially in our liver patients and our kidney patients. With this active metabolite known as londanasine, that also can cause seizure activity. So in any patient where we're worried about the elimination of this drug with this active metabolite building up, we have to be careful that we do not give excessive amounts of this drug or over a long period of time or as a continuous infusion, we don't wanna see this drug's metabolite build up causing the patient to seize. The next agent of our non-depolarizing muscle relaxant class is sesatricurium. And remember how I said atricurium is a combination of about 10 different isomers of that molecule? Well, sesatricurium is one of those isomers. So sesatricurium, structurally related to atricurium, although it is an isomer, it's actually much more potent than atricurium and because it's much more potent, we have to give less of it. When we give less amounts of this drug, what it does is it takes a little bit longer for it to work. It's got a slower onset of action. However, one of the benefits is because we're giving less of it, we see a lot less of that active metabolite, laudanosine, build up and thus we're not as concerned about provoking seizures in patients if we were to give this drug over and over in large doses for long periods of time. Sesatricurium is also metabolized by Hoffman elimination. Again, an acidic drug that's injected into a more basic human who is at a higher temperature than say room temperature. That's what causes this drug to degrade or metabolize essentially. Because both atricurium and sesatricurium do get metabolized by this Hoffman elimination, they are ideal for renal and liver patients. However, with atricurium, we have to be very careful because of that active metabolite. That's why it's not indicated for renal or liver patients and it really isn't used clinically all that much anymore. Sesatricurium also doesn't cause histamine release in the clinical doses that we're giving. So great for not causing any kind of cardiac problems, any kind of blood pressure issues, any kind of allergic responses. Much, much better drug in that regard, especially when you consider it doesn't have as much londanacine building up and it's ideal thus for our renal and liver patients. Vecuronium is the next nondepolarizing drug that I'll discuss. It comes typically as a vial of powder because it's actually very unstable in its solution form. So we usually reconstitute vecuronium. It comes in myriad preparations. So always check the amount of vecuronium that it comes in as a vial. You can then mix it to whatever concentration you want, but we typically mix it to about one milligram per cc. Vecuronium is a nondepolarizing agent. Again, like our atracurium and sesatricurium, you're not gonna see the fasciculations that you do with succinylcholine. This nondepolarizing agent usually lasts about 30 to 45 minutes. It's considered an intermediate acting or intermediate duration nondepolarizer. The onset time is very similar to atracurium in that it takes about three minutes to work for that patient to become relaxed. We see that with this drug, we don't have Hoffman elimination. It's primarily metabolized and eliminated by the liver and excreted in the bile. There is some excretion that happens via the renal system. So we do particularly pay attention to our renal and liver patients. Again, the drug of choice for muscle relaxation in liver and kidney patients is typically sesatracurium. Vecuronium, because it relies on the liver and kidneys for metabolism and excretion, we typically want to be very careful with Vecuronium in those patient populations because it has an active metabolite, 3OH, which can cause prolonged relaxation or paralysis. Why is that bad, you say? Well, let's say the case is over and you've given so much Vecuronium to the patient that this metabolite has built up and the patient's still paralyzed, right? This is why we have to time these drugs. This is another reason why anesthesia is truly an art because you have to know how long the drugs are gonna last, if they have metabolites. Good thing for Vecuronium is that the metabolite doesn't cause seizures. It just can cause excessive or prolonged paralysis. Rocuronium is the last non-depolarizing agent I'm going to discuss. It is widely used. It's also considered an intermediate-acting, non-depolarizing muscle relaxant because it lasts about 30 to 60 minutes. It's very stable in its solution, in its vials, so it does come as a solution that you draw for intravenous administration. It has a faster onset than Vecuronium, so it takes slightly longer than succinylcholine, but that's why Rocuronium can be used for rapid-sequence inductions. It has one of the fastest onsets of our non-depolarizers, so when we have to rapidly intubate a patient because we're worried about any stomach contents coming up and going down into the lungs causing aspiration pneumonitis or anything like that, we will use Rocuronium and or Sucs for these rapid-sequence inductions. It is less potent than Vecuronium. We see that metabolism is primarily by the liver. It's excreted in the bile, and we also see some of it being excreted via the kidneys unchanged. It does have a high incidence of allergic reactions compared to our other non-depolarizers, again, keeping in mind that succinylcholine and Rocuronium are the two most frequently cited neuromuscular blockers that are associated with allergic reactions. But again, Rocuronium, a great drug for our rapid-sequence inductions, certainly great in patients where we would be worried about high levels of potassium happening after a dose of succinylcholine. So you can see why drug choice is definitely an art, and it certainly requires knowing the drugs before we start administering them for our general anesthetics. This summative table includes agents that are no longer used clinically, however, are good for historical context. You'll see that over the years, different muscle relaxants have been developed by different companies for varying reasons, whether it be a faster or slower onset or a longer or shorter duration. They all have their pluses and minuses. As you just learned, metabolism is something that is of concern and makes, obviously, Cisatricurium a little bit more appropriate for our liver and renal failure patients. Certainly, when we need a longer acting agent for a very long surgical case, you would want to choose a drug that would, say, have a longer duration of action, right? You don't want to keep administering these drugs, if you're in a 12 or 14-hour case. So I have different intubating doses. Again, that would be what we would give after our Propofol or Atomidate or Ketamine, the time to max blockade, as well as the clinical duration of these agents. Keep in mind, I've highlighted the drugs we most commonly use now in anesthesia. I have some agents here that are for historical context, like our Tubocurari and our Pancuronium. For those of you interested in the rapid sequence induction dose of ROCK, that's what that RSI is on the table. ROCKuronium is the only nondepolarizer that we typically use for rapid sequence inductions. Again, when we need a very quick-on paralysis in the patient so that we can hopefully prevent aspiration from happening if the patient has a full stomach, that's when we would choose to do a rapid sequence induction. Take a look at the table. Certainly let me know if you have any questions. Speaking to the pharmacokinetics, more specifically the elimination and metabolism of our neuromuscular blocking drugs, we see these drugs primarily stop working or they don't have effects anymore, not because the drug is metabolized, but because the drugs redistribute off the nicotinic acetylcholine receptors. Once the drug leaves the nicotinic acetylcholine receptor, an action potential can then trigger the depolarization of the skeletal muscle, that postsynaptic skeletal muscle at the neuromuscular junction, and that muscle's no longer paralyzed. It's gonna twitch. The patient will be able to move that skeletal muscle. So with just single-dose drugs or an intubating dose, usually these effects are triggered from the drug leaving that nicotinic acetylcholine receptor. Most of our non-depolarizing agents, again, non-depolarizing agents being vecuronium, rocuronium, cysatracurium, atracurium, those muscle relaxants are affected in some way by the kidneys. So in our patients that have impaired renal function or are in end-stage renal disease, we will see a prolongation of these drugs in those patient populations. Does that mean the patient's going to be paralyzed for hours and hours? No, it just means that you can expect either seconds or minutes longer than what is printed in the package inserts of these drugs. Succinylcholine is different. Succinylcholine is our depolarizing agent, and sucs is inactivated by plasma cholinesterase after it redistributes off that nicotinic acetylcholine receptor. Atracurium and cysatracurium are different from rocuronium and vecuronium in that they are degraded and eliminated via Hoffman elimination. Remember, we discussed that. And atracurium has the added benefit that it can also be degraded by ester hydrolysis. Vecuronium and rocuronium, those are eliminated via the kidneys and in some part by the liver. Wrapping up the pharmacokinetics and pharmacodynamics of our neuromuscular blocking drugs, these drugs are positively charged molecules, which if we remember way back to our cellular physiology days, really reach back in that brain and remember those cellular physiology days, we remember that molecules that are positively charged means that they usually can't pass lipid membranes. And if these drugs can't pass lipid membranes, we can expect that there's not gonna be any passage of these drugs through the blood-brain barrier. And thus, we're not gonna see central nervous system activity in this drug class. Remember, these drugs aren't keeping the patient asleep. They're not anesthetics. They're purely for relaxing the patient or paralyzing the patient. We see that these drugs have a volume of distribution that's primarily the extracellular space. And related to heart function, the onset of these drugs are very limited to the cardiac output of the patient. Meaning, if the patient has a sick heart and a very poor cardiac output, it's going to take these drugs longer to reach those nicotinic acetylcholine receptors because that's how these drugs are gonna work. They have to be pumped to the skeletal muscle by the heart to actually attach to that nicotinic acetylcholine receptor. Practically speaking here, if we take a look at our pediatric patient population, children typically need higher dosing because they have a high volume of distribution, but they also have more sensitive nicotinic acetylcholine receptors. This means in kids with our standard dosing, they're going to have longer periods of paralysis. They also have an interest in cardiac physiology, right? Our PEDS population has higher heart rates, higher cardiac indexes. So what does that mean? With our neuromuscular blocking drugs, they're gonna have a faster onset time. Our older patients or our geriatric patient populations actually have prolonged distribution and elimination kinetics of this drug class because they have decreased organ function. As we get older, our kidneys don't work as well, our livers don't work as well. So especially with ROCK and VECURONIUM, we can see prolongation of these drugs. Again, not by hours and hours, but perhaps seconds, minutes, you're gonna note a prolonged time. Obese patients also exhibit prolongation of these drugs, primarily ROCK and VEC again, because they have a decrease in elimination. Now, our nondepolarizers should be dosed in our obese population on ideal body weight. For our depolarizing succinylcholine, we're dosing it on actual body weight. Now, I wanna highlight too in this slide that with any case that involves muscle relaxation or this drug class, the neuromuscular blocking drugs, the American Association of Nurse Anesthesiology advocates that CRNAs monitor the level of paralysis. And while it's above and beyond the scope of this pharmacology lecture to go into neuromuscular blockade monitoring, many ICUs are already implementing this monitoring. And certainly, if you want more details on monitoring this drug class and actually measuring the level of paralysis, I'll refer to you to the nurse anesthesia textbook by Elisha Heiner and Nagelhout. I'll also emphasize that with the exception of succinylcholine, remember, succinylcholine doesn't need to be reversed. It's a depolarizing agent and it wears off very quickly. All of our neuromuscular blocking drugs are reversed at the end of a general anesthetic. Atrocurium, cysatrocurium, rocuronium, vacuronium. These drugs need to be reversed with agents at the end of the case, so the patient is strong, breathing on their own, and able to protect their airway with good coughs and airway reflexes. So we've reversed our non-depolarizing muscle relaxants, typically with an anticholinesterase and anticholinergic. If the agent of relaxation throughout the case was rocuronium or vacuronium, you also have Sugamidex that can reverse those two drugs. So again, the reversal of our non-depolarizing muscle relaxants is above the scope of this lecture, but again, I will refer you to that great nurse anesthesia textbook. Following the continuum of our anesthetic care, after we've premedicated the patient with a benzodiazepine like Midazolam in the preoperative area, we've brought the patient back to the operating room, we've attached the monitors, we began our induction, right? The induction sequence, as we call it, that's the pharmacologic sequence and timing of drugs that push the patient to sleep, usually begins, again, with pre-oxygenation followed by the drugs we just reviewed, an opioid, an induction agent, and then a neuromuscular blocking drug to facilitate an easier instrumentation of the airway. After we do our direct laryngoscopy, we take a look with our laryngoscope and we place an endotracheal tube. What then? What are we gonna do? We have to secure that airway, usually with tape. And what's gonna keep the patient asleep for the surgical case? Well, there's several ways to keep a patient asleep during surgery, but one that I'm all sure you're very interested in, because this is a class of drugs that's very, very different from anything you've administered as an RN, those are inhalational agents. Modern day inhalational anesthetics are described as either being volatile or gaseous. A volatile inhalational agent means the agent is liquid at room temperature, it evaporates in a vaporizer in our anesthesia machine, and the gas that it emits through the evaporation process is the anesthetic. An example of a volatile agent would include something like seboflurane. A gaseous inhalational agent means the inhalational agent exists as an anesthetic agent in gas form at room temperature. And an example of that would be nitrous oxide. Inhalational anesthetics, both volatile agents and our gaseous agent, nitrous oxide, are substances that are brought into the body via respiration and lungs and are distributed through the blood and into different tissues. The main target of these gases, these inhalational anesthetics, is the brain, the central nervous system. Unlike the typical parenteral drug that you inject into a patient's IV, where absorption, distribution, metabolism, and elimination describe the pharmacokinetics of those drugs, inhalational anesthetic pharmacokinetics are primarily just uptake, distribution, elimination. That's how these drugs work. I include biotransformation here because there is a little of that occurring, as you can see by the very paltry amounts of inhalational agents that undergo very, very minimal metabolism. But be aware that the minimal metabolism of these drugs is not what causes these drugs to stop working. These drugs stop working because they are breathed out. They are expired from the patient. They start working because we turn on the gas and they are breathed in, and they stop working because the gas is turned off and the remnant gas is then breathed off, ventilated, expired off, and out of the patient. The basic task of anesthetic administration involves taking a drug supplied as a liquid, vaporizing it in an anesthesia machine vaporizer, and delivering it to the patient's brain and other tissues via the lungs. So you can imagine that if the target organ of these inhalational gases are the brain, that you can expect that the side effects, the pharmacodynamics of this drug class are going to be primarily nervous system related. We see in the central nervous system that these drugs affect consciousness. We use them because they provide unconsciousness in our patient population. There's no sense in being awake for your surgery. It's probably very scary, I would imagine. They do provide some analgesia. They provide amnesia, because there's no sense in remembering any of this either, and a little bit of immobility as well. You can see where in the central nervous system these side effects or the pharmacodynamics are working. Certainly the sites of action in the CNS are listed on this slide. The mechanism of action is a little bit under scrutiny, and I'm gonna just say quite unknown. So you can read about kind of the general consensus of how these drugs are working. The main gist of it is just that these drugs enhance inhibitory pathways and diminish excitatory pathways. Now, you would be asking, how do we dose these drugs if they're gases, right? We can't use a weight-based dose like milligrams or grams like we're used to giving with our IV drugs, but we can certainly use a concentration to describe an amount of gas. You'll note that there are numbers on the tops of these anesthesia vaporizers pictured here on this slide. The yellow one is a vaporizer for sevoflurane, and the purple one would be for a drug like isoflurane. Those numbers are percents, and as you turn the dial up on the vaporizer, you're increasing the concentration of gas you administer to the patient. But how much gas do we need to give a patient? We use a percentage amount known as the MAC, the minimum alveolar concentration, to guide our administration of these gases. The MAC percentage of an inhalational agent is the concentration or amount of gas that will produce surgical anesthesia in 50% of patients. That means they're anesthetized, and they're not going to move to surgical incision. Each agent has its own unique MAC percentage value, and thus you can tell that some of the agents listed here on this slide are more, and some agents are less potent than each other. What I mean by that is that they all have different potencies. If you need a higher percentage of gas to keep 50% of the patient population from moving on surgical stimulus, that's the definition of MAC, that means that the gas is less potent than a gas that can accomplish immobility using a lower percentage of gas. The potency of an inhaled agent is measured by its lipid solubility. The lipid solubility of an inhaled agent is denoted by its oil gas partition coefficient. So potency is equal to lipid solubility, and that means that it easily crosses membranes, one of the very important ones being our blood-brain barrier. There are situations, conditions, and pathophysiologic states that do increase or decrease MAC values. And in general, factors that decrease central nervous system metabolic activity, neurotransmission, or central nervous system transmitter levels, all are situations that will decrease MAC, meaning you don't need to give as much inhalational anesthetic to keep the patient asleep. So we notice that in our geriatric patient population, those humans that are increased age, MAC decreases about 6% per decade of life. So geriatric patients don't need as much gas to stay asleep. Patients in metabolic acidosis, or hypothermic. Patients that have already received sedative hypnotics, like our induction drugs. Any patient that also has other anesthetics on board, like dexmedetomidine. Patients on alpha-2 agonists and opioids. Patients that are acutely intoxicated with ethanol. They've gone out drinking. If they're already half in the bag because they went out drinking, they don't need as much gas to stay asleep. Patients that are hypoxemic. Hyponatremic. Anemic. They're hypotensive. Patients who are pregnant. And those patients on lithium all do not need as much anesthetic gas to stay asleep. Those conditions that increase the amount of gas we need to give patients are generally those factors that increase central nervous system metabolic activity, neurotransmission, and any kind of CNS neurotransmitter levels. These are all conditions that make it so that we need to give a higher percentage of inhalational agent to these patient populations or those patients that have these different conditions. Those conditions that increase MAC are those patients like pediatric patients, hyperthermic patients, hyperthyroidism patients that are in perhaps thyroid storm, hypernatremic patients, patients that are on CNS stimulants, and those that chronically use ethanol alcohol or are alcoholics. These patients all need more anesthetic gases to stay asleep for their surgical procedures. Doing a deeper dive into the pharmacodynamics of these inhaled anesthetic drugs or anesthesia gases, let's break up the effects by system, starting with the cardiovascular effects of our inhaled gases. These produce a dose-dependent effect on the cardiovascular system. And again, what does dose-dependent means? It means that the more you give, the more profound effect you're going to have on the heart and the vascular system. With our inhaled agents like seboflurane, isoflurane, desflurane, we note that the blood pressure goes down. It lowers because of systemic vascular resistance decreasing. That means the patient's vasodilating. That's a decrease in SVR. Thus, the blood pressure is lowered. We also see there is some baroreceptor and myocardial depression with these agents. Nitrous oxide, on the other hand, generally has a minimal effect on the blood pressure, the heart rate, the vasodilation or peripheral vasodilation, systemic vascular resistance, and cardiac output. But it does have sympathomimetic effects, meaning in certain doses and in certain cases, nitrous can raise these hemodynamic variables. Heart rate in general tends to slow with our agents like iso and sebo, although that's usually not the case during excitement phases of anesthesia. And when you get into school, you will learn about all of the different phases of general anesthesia. I didn't mention desflurane there because desflurane is unique. Desflurane actually can produce significant tachycardia in patients when you really increase that vaporizer dose and you try to get that concentration of desflurane to rapidly rise in patients. You'll note that the heart rate starts to increase as you really increase that dial with desflurane. Moving to the pulmonary or respiratory system, we can see that with our inhaled agents, again, we have that dose-dependent effect. And again, what does that mean? It means the more we give, the more profound side effects we're gonna see. It's no different in our pulmonary or respiratory system. So if we give a lot of isoflurane, a high, high percentage of sebo or desflurane, what we're going to see when we dial that percentage up on that vaporizer really high is that if the patient is spontaneously breathing through a laryngeal mask airway or LMA, the patient will eventually become apneic from those really high percentages of the gas. Again, dose-dependent. That means that the higher or the more we give, obviously the more profound effect we're gonna see and that effect is apnea. The exception to this is nitrous. Nitrous actually increases respiratory rate. Overall, our patients when they're exposed to our inhaled agents are going to have a decreased tidal volume. So they're gonna have short, shallow breaths if they're breathing spontaneously through that LMA. We're gonna note that CO2 is retained and overall, the minute ventilation is going to go down in our patients. Of note, let me just say that seboflurane is a great drug for bronchodilating our asthmatic patients. It relaxes smooth muscle, it bronchodilates. It's a great, great treatment for any wheezing patient. If they're spontaneously breathing through an LMA and they start wheezing, dial up your sebo. It'll get rid of that wheeze. Please note, iso and des are somewhat irritating. So we don't typically like giving those through LMAs. Moving more peripherally away from our heart and lungs, we see that our inhaled anesthetic gases slow GI emptying. They overall slow GI function down. The other thing they do is they peripherally vasodilate or they decrease systemic vascular resistance. That in turn will decrease our hepatic blood flow in patients. So keep that in mind if you're dealing with any liver dysfunction patient. You obviously don't want to cause any hypoxic injury to any remaining good functioning liver tissue. As far as the kidneys are concerned, all of our volatile agents, and again, volatile agents are those agents like seboflurane, desflurane, isoflurane. All of those volatile agents decrease SVR, systemic vascular resistance. And when we do that, blood pressure comes down. When the blood pressure comes down, that obviously decreases our renal vascular resistance. And this is the primary mechanism by which our patients will have a lower urine output in the OR. We also see that renal blood flow comes down from that decrease in renal vascular resistance and blood pressure, as well as glomerular filtration rate. That also will be decreased with our inhaled anesthetic acids. So we've gone through a typical general anesthetic, and you now have a basic understanding of some of the drugs we use in our nurse anesthesia practice. It's been an adventure, everyone, and thankfully, it looks like I haven't put you to sleep, so that's good. Here are just a few of the texts we use at the Kaiser Permanente School of Anesthesia. The information I've presented to you has come from these texts and those that I've cited on the slides. No matter where your nursing journey takes you, remember that you have infinite possibilities. Nurse anesthesia is just one of them. I do, however, hope you'll consider joining us, and if you do decide to, I hope to see you at the Kaiser Permanente School of Anesthesia. I wish you all the best. Take care, everyone.

pharmacology

general anesthesia

nurse anesthesia

benzodiazepines

midazolam

induction agents

propofol

neuromuscular blockers

succinylcholine

rocuronium

inhalational anesthetics

CRNA

cardiovascular stability

respiratory effects

Sarah Jerome

nurse anesthetists

induction drugs

ketamine

opioids

GABA receptors

opioid-sparing techniques

isoflurane