Ketamine Anesthesia Uses, Effects & Mechanism of Action w. Dr. Kelly Elmore, Mary Baldwin University

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Dive deep into Ketamine, unraveling its pharmacokinetics and mechanism of action plus learn about its unique properties that make it a game-changer in managing pain & mental health disorders in ketamine-assisted therapy.

By blocking NMDA receptors, ketamine effectively reduces excitatory signals in the central nervous system, providing relief where traditional treatments may falter. Its ability to maintain airway patency and promote bronchodilation is crucial for anesthesia, especially beneficial for patients with respiratory issues.

Under the expert guidance of Dr. Kelly Elmore from Mary Baldwin University, explore the versatile applications of ketamine and learn about its impact on both medicine and mental health therapy.

Join the Free CSPA Community! Connect with a network of Aspiring CRNAs, Nurse Anesthesia Residents, practicing CRNAs and CRNA Program Faculty Mentors here: https://www.cspaedu.com/community

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Get access to application & interview preparation resources plus ICU Educational Workshops that have helped 1,000s of nurses accelerate their CRNA success. Become a member of CRNA School Prep Academy: https://cspaedu.com/join

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Ketamine – Uses, Effects & Mechanism of Action w. Dr. Kelly Elmore, Mary Baldwin University

A Brief History of Ketamine

Hi, and welcome to everyone at CRNA School Prep Academy. My name is Dr. Kelly Elmore. I am the Assistant program director at Mary Baldwin University’s nurse anesthesiology program, and today I will be presenting on the drug ketamine. It’s a great drug, it’s a unique drug, has a variety of uses. Many of you have probably used it in practice or know of it, so we’ll take a little bit of a closer look at ketamine today. So my presentation is termed “A Knack for Ketamine.”

So we’ll start with a quick intro into the history of ketamine. We actually would need to start with phencyclidine. Phencyclidine was synthesized by chemists in the 1950s, and it was tested on animals used in veterinary medicine, and what they found with phencyclidine is that it would cause these drunken states, catalytic states at times and anesthesia and even times a lot of delirium in a variety of animals, rodents, dogs, pigeons, cats, et cetera.

In order to transfer the use of a drug like that into human populations, they needed to find one that had less of those undesirable side effects. So about a decade later or so, they started to use ketamine, which is a shorter acting analog of phencyclidine with human patients. That started around the 1960s.

Ketamine’s Pharmacological Profile

Ketamine is usually described or classified as a dissociative anesthetic. We’ll talk a little bit more about what that means and looks like later, but if you’re comparing it to other anesthetics like propofol, we tend to call those depressant anesthetics.

The mechanism of action is a little bit different. They’re basically both adjusting the way neurons can communicate in the central nervous system, especially in the brain. But ketamine is typically considered a dissociative anesthetic. It has great analgesic properties as you all know, it’s been used and is being used more and more in the treatment of various mental health disorders. It’s a great sedative. It has been used to treat opioid tolerance and chronic pain syndromes.

The World Health Organization, every couple of years, they release their list of essential medicines. So the last one was in 2023, and ketamine has consistently been on that list of essential medicines, particularly as an anesthetic. The World Health Organization formulates that list by looking at what are the priority health needs of populations based on public health, the relevance of those drugs to public health, evidence of efficacy and safety, cost-effectiveness and disease prevalence for those populations.

Ketamine Pharmacokinetics

Ketamine: Ketamine is water and lipid-soluble. It easily transfers across the blood-brain barrier.

Next, we’ll look at structure and pharmacokinetics. The majority of you who have maybe used ketamine in your clinical practice are likely using the racemic mixtures. So with the racemic mixture, we have both isomers, the S(+) plus and the R(-) forms of ketamine. There are some countries that have that S(+) formulation isolated. The benefit of having just S(+) ketamine is that it has greater anesthetic potency. It has a higher affinity for the beneficial receptors, which we’ll talk about.

It’s the NMDA receptor, less of the cardiac stimulating effects, motor effects, psych effects, and typically a quicker recovery than the R(-) isomers. So S(+) is beneficial, but again, typically what we see in the US what’s manufactured and marketed for us is a racemic mixture of the two. So we get some of the good mixed with some of the less desirable.

Ketamine is water and lipid-soluble. We do love our lipid-soluble drugs in anesthesia because we want those drugs to easily cross those lipid bilayer membranes that surround our cells and get to the sites of action, particularly the central nervous system. So ketamine easily transfers across the blood-brain barrier. It is metabolized by the liver by your CYP 450 enzymes and liver blood flow can affect the rate at which your body would metabolize ketamine.

It does have an active metabolite, so norketamine has about a third of the pharmacologic activity of regular ketamine as a metabolite. So if you were to continually give bolus doses or maybe an infusion of ketamine in the acute period, that metabolite could potentially start to accumulate. It really only becomes an issue in a patient that maybe has renal dysfunction because that can affect the body’s ability to clear that drug.

We can give ketamine in a variety of routes, intravenous intramuscular, intranasal GI routes, and even by bone you can give an intraosseous sometimes probably done in emergency departments. Once you start to go in the by-mouth route, you start to involve the GI system. Ketamine does have a very high first pass metabolism, meaning your liver takes some of that initial dose and will metabolize it before it can even get to its sites of action. So that’s something that we have to be mindful of. The bioavailability of giving ketamine by mouth or by rectum is going to be a lot lower than if we give it intravenous or intramuscular, for example.

Ketamine Mechanism of Action

Next, we’ll look at mechanism of action. So the mechanism of action, just like several of our anesthetics or many of our anesthetics is not fully understood. However, we do know a lot and we know that primarily ketamine is an n-methyl-D-aspartate. That’s NMDA receptor antagonist.

So NMDA receptors are highly active in your central nervous system. They bind a neurotransmitter called glutamate. It causes these excitatory reactions in the central nervous system, so ketamine helps to block some of that excitation. It is also an agonist weakly at opioid receptors like the mu receptor, so it means that it would bind a mu receptor and can cause a weak activation of that which is beneficial for pain response.

NMDA receptors are highly active in your central nervous system. They bind a neurotransmitter called glutamate, which causes these excitatory reactions; ketamine helps to block some of that. Share on X

For example, ketamine blocks voltage-gated ion channels like sodium and calcium. It does have some dopamine receptor agonism, which might produce euphoria that might be considered a beneficial effect in some populations. It does suppress inflammatory mediator production by neutrophils and also even has some weak GABAA receptor activity, and GABAA is the primary receptor that’s targeted by many of our other IV anesthetics like propofol.

So NMDA receptor antagonism, again, that’s the primary. It’s very helpful. For example, NMDA receptors and glutamate are present and active in pain signaling. So when you encounter a noxious stimulus from your environment, the glutamate is going to target that NMDA receptor and continue to transmit that pain signal to the brain and from the brain in the spinal cord in the periphery.

All of these systems will kind of connect while ketamine can help reduce or inhibit that response to a noxious stimulus. So that can help someone, it decreases their ability to sense and interpret a painful stimulus.

Dissociative Anesthesia

Dissociative anesthesia. So now we’re back to that term. What does that mean exactly? Typically, it’s described as someone detaching from their environment. So with dissociative states, we are basically dissociating certain cortical areas, thalamic areas of the brain which are going to help replay cellular neuronal communication it’s where some of our sensory functions are. We’re kind of disassociating that from limbic systems and other areas of the brain that are involved in awareness. So you are having a hard time interpreting the stimuli that are around you.

Associated with this dissociative state is also a cataleptic state, so the patient might have muscular rigidity, increased muscle tone, fixed postures, nystagmus gaze is quite common. So with that gaze, their eyes are open, they may appear alert, but they really are not focusing on any particular thing. Their eyes will start to kind of shift to the side kind of in a slow distracted gaze. Non-communicative, these patients generally are not going to respond to anything in their environment. They’re not going to communicate with you.

However, the dissociative anesthesia state is associated with profound analgesia and amnesia, so it doesn’t appear that these patients are in distress when we induce a dissociative anesthetic state. And of course this is going to depend on the amount of ketamine that is given, so we would have to give it in a high enough dose to start that dissociative anesthetic.

Ketamine Risks

As far as the effects, it can be beneficial in some neuro patients, pediatrics, agitated psych patients or anyone else that’s uncooperative, for example, if they need a procedure done, maybe they do not require general anesthesia, but some degree a sedation or anxiolysis or something like that. So ketamine might be used in certain populations for those benefits.

That does bring us to delirium. Again, this is typically a dose dependent response with ketamine. Like I mentioned before, not as high, as what’s associated with cyclidine, but it definitely is a side effect of ketamine because we are interrupting that person’s ability to interpret and sense the stimuli in their environment. This can actually increase their risk for further delirium. Patients tend to report vivid dreams like purple hippos or things like that. That’s actually a dream that I had heard a patient report. I didn’t just make that up. And hallucinations are common.

If we have progressed into a delirium state with ketamine, it could potentially cause psychiatric distress. Definitely delirium has risks for anyone, but certain populations are very sensitive to delirium like the older adult, and so that could present some potential problems. Higher risk would be female patients, older age and adults, certain personality disorders, maybe some other mental health disorders could be at higher risk.

Ketamine: Some benefits of ketamine include stable vital signs and high patient satisfaction.

If you’re also administering other sedatives and anesthetics, which again are affecting the central nervous system that puts someone at higher risk, as well as just using, like I said, those higher doses of ketamine. Usually we’re getting into anesthetic doses that we would tend to use in the operating room to induce maybe a general anesthesia state that’s going to put someone at higher risk for delirium after surgery.

Analgesia, one of the great benefits of ketamine, often used for acute pain. So in anesthesia we love it. Of course, postoperatively it’s beneficial for our patients. Emergency departments often use ketamine as an analgesic. Burn units, ICUs, variety of different areas you might see it used. It’s going to typically be used in what we call a sub-anesthetic dose, so that’s much lower than what we might use to put a patient to sleep.

With ketamine, it has been associated with high patient satisfaction and stable vital signs, so there’s some benefits. When we look at chronic pain, it has a role possibly in cancer patients because it has those opioid-sparing effects and oftentimes cancer patients are on high dose opioids. Non-cancer pain, they’ve looked at patients with complex regional pain syndrome. It helped alleviate symptoms in phantom limb pain.

It may even alter some of the mechanisms associated with fibromyalgia and ischemic pain. And of course it is used often in opioid tolerant patients, in those with opioid abuse disorders, just because it’s an alternate mechanism to help with their pain that can reduce their opioid use.

Ketamine Pharmacodynamics

So looking at the pharmacodynamics, how ketamine might affect a few of the other systems. We’ll start with cardiovascular. Ketamine is actually sympathomimetic. It reduces the reuptake of norepinephrine, so we have excess circulating catecholamines that can then target your sympathetic nervous system.

However, ketamine is also a cardiac depressant directly, so if you have a patient that does not have a lot of catecholamines to be released and to help stimulate the heart, the cardiovascular centers and other areas, ketamine in and of itself could actually cause some negative inotropic and in some severe cases, even cardiovascular collapse.

So it does rely on catecholamines in order to stimulate the heart, but when it does stimulate the heart, it usually does cause an increase in blood pressure, heart rate, cardiac output and things like that. It’s usually kind of a limited effect. You might see that patient return to baseline after about 20 minutes or so, some amount of time.

Central nervous system effects is cerebral vasodilator, so it’s going to increase blood flow in the brain. It can actually be associated with a higher risk for increased intracranial pressure. It could possibly cause some CNS excitation as well. However, they have studied the use of ketamine in neuro patients like traumatic brain injury and have found that it may have protective effects against seizure development and cerebral ischemia. So you may still be able to use it beneficially in the neuro population.

We absolutely love ketamine for its ability to bronchodilate as well as help patients maintain the tone in their airway, upper airway, and help maintain patency of that airway. Share on X

As far as pulmonary and airway, we absolutely love ketamine for its ability to bronchodilate as well as help patients maintain the tone in their airway, upper airway, and help maintain patency of that airway. Generally, their ventilatory response is not diminished too much with ketamine alone, unless we are adding in other anesthetics or CNS depressants, then that might be affected. But otherwise it’s very beneficial on those systems

Ketamine Side Effects and Cautions

Side effects and some other cautionary tales. For ketamine, it does increase the risk of nausea and vomiting. It also has a high abuse potential. You all probably know it is a popular club or rave drug. It can easily be manufactured on the streets. People use it in a variety of routes there. It could be snorted, smoked, mixed into drinks, things like that.

They have studied and they keep their eye on ketamine as a street drug that might be combined with anything from a cigarette or marijuana to amphetamines and cocaine. So it definitely has high abuse potential and that is some of the reasons why it might be slightly limited in the mental health populations as an outpatient therapy.

We did talk about those possible cardiac effects. So of course in critically ill patients, shock states, unstable cardiac patients, anyone who might have some of that catecholamine depletion, we try to stay away from ketamine or at least high dose ketamine in those patients. And then some psych and mental health disorders, it could possibly exacerbate their symptoms.

Ketamine Therapy

Psychedelic assisted psychotherapy, ketamine assisted therapy, this is kind of the more recent hot topic for ketamine, is its ability to treat and have some success in otherwise treatment-resistant disorders, especially ones that are presenting in a very severe way like depression, PTSD and suicidal ideation.

Ketamine: Psychedelic assisted psychotherapy or ketamine assisted therapy refers to its ability to treat and have some success in otherwise treatment-resistant disorders, especially ones that are presenting in a very severe way like depression, PTSD and suicidal ideation.

Typically in those cases, patients may come in for a couple of months of therapy. They may receive several infusions a month where they go into an office, they receive ketamine infusion. It’s usually again, a sub anesthetic dose. It’s usually a lower dose, and then someone might guide them through a “trip.” So that dissociative state might be induced to some degree and ideally a mental health practitioner would be present to help guide them through maybe some distressing moments in their life or other things that they maybe need some improvement in dealing with.

Typically, they have seen that patients will possibly develop sensitization and tolerance to ketamine infusions, so it does require some titration and just kind of playing around and making sure that patient’s on the appropriate regimen. However, they have had a lot of success.

Generally, if this is given in some sort of office or non hospital type setting, it requires a couple of providers for monitoring that patient and at least one provider should be advanced cardiac life support, trained, trained in airway and other advanced monitoring just to keep those patients safe. They have been researching ketamine and schizophrenia modeling, and that’s because ketamine has been shown to actually cause some symptoms that are similar or the same as those encountered in patients with schizophrenia. So researching the drug might help them gain a better understanding of that disorder.

S-ketamine, if you’ve heard of that, it is the FDA approved nasal spray that has been used in some of the mental health therapeutic regimens for treatment resistant depression. Typically, that patient has had some sort of record of failed therapies and then they would also of course be taking other oral antidepressants in addition to s-ketamine, but they’re showing a lot of promise with that particular drug regimen.

So in conclusion, ketamine is a very unique anesthetic. It has many beneficial properties. We love the anesthesia, the sedation, the analgesia. It’s very useful for CRNAs in anesthesia practice, and of course we absolutely love when it can help maintain some of that cardiopulmonary stability and airway patency in our patients.

Mary Baldwin University Nurse Anesthesiology Program

A little intro to Mary Baldwin University’s Nurse Anesthesiology program, if you’ve never heard of us, we are a fairly new program, so we will be starting our third cohort in fall semester of 2024 this year; the university is located in Stanton, Virginia, and our college is Murphy Deming College of Health Sciences, which is a few miles away in Fishersville.

We currently accept 25 students per cohort. It is a hybrid three year DNP program. The way it’s kind of structured, just to give you a quick idea, is that the very first year is all online, so it’s taking some of the DNP courses that year. You’re taking pathophysiology and pharmacology, chemistry and physics courses like that in an online setting, and some of those courses are synchronous, some might be asynchronous.

Then for year two and three, you would have to move if you were not already present in Virginia or North Carolina, closer to one of our primary clinical sites. But otherwise, we have a variety of clinical sites and experiences available in those Mid-Atlantic states.

We do have simulation and cadaver labs, so our students do a full year of simulation lab. That was just a brief introduction to our program, but if you would like more information, we do host virtual information sessions the last half of the year. These are monthly from July to December, so our next one will be October 8th. They’re usually on a Tuesday, usually the first or second Tuesday of the month. You can find the schedule of virtual information sessions at our website: https://marybaldwin.edu/programs/nurse-anesthesiology-dnp/

And that is really all I have for you today. I really appreciate this community and the ability to speak with you today. Thank you so much!

Important Links

Join the Free CSPA Community! Connect with a network of Aspiring CRNAs, Nurse Anesthesia Residents, practicing CRNAs and CRNA Program Faculty Mentors here: https://www.cspaedu.com/community

Get access to application & interview preparation resources plus ICU Educational Workshops that have helped 1,000s of nurses accelerate their CRNA success. Become a member of CRNA School Prep Academy: https://cspaedu.com/join

Get CRNA School insights sent straight to your inbox! Sign up for the CSPA email newsletter: https://www.cspaedu.com/podcast-email

Book a mock interview, resume or personal statement critique, transcript review and more: www.teachrn.com

Attend an upcoming Virtual Information Session with Mary Baldwin University Nurse Anethesiology Program: https://marybaldwin.edu/programs/nurse-anesthesiology-dnp/

Special Note- Application Deadline for their next cohort is 12/15/2024!