Ep.42– Dexmedetomidine For The FRCA Primary

GasGasGas – The FRCA Primary Anaesthetics Exam Podcast

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Classification & Basic Properties

Generic Name Dexmedetomidine
Brand Names Precedex (USA), Dexdor (UK)
Chemical Class Imidazole derivative
Molecular Weight 200.28 g/mol
Presentation Clear, colorless solution (100 mcg/ml)
Stereochemistry D-enantiomer (S-configuration by Cahn-Ingold-Prelog)
IntroductionUSA (1999), UK (2011)

Pharmacodynamics of Dexmedetomidine

Mechanism of Action

Comparative Receptor Selectivity – α2:α1 Selectivity Ratio

• Dexmedetomidine 1620:1
• Clonidine 220:1

i.e. Dexmedetomidine demonstrates approximately 8-fold greater selectivity for α2 receptors compared to clonidine.

Dexmedetomidine functions as a highly selective α2-adrenoreceptor agonist, binding to Gi-protein coupled receptors. This initiates a cascade where:

1. Gi subunits inhibit adenylyl cyclase
2. Reduced intracellular cAMP production occurs
3. Potassium channels remain open (less inhibition)
4. Cellular hyperpolarization results from K+ efflux
5. Neural signalling becomes impaired

Sites of Action

• Locus Coeruleus : Arousal and waking Noradrenergic (part of the Reticular Activating System)
• VLPO Nucleus : Sleep maintenance GABAergic
• Raphe Nuclei : Mood, pain modulation Serotonergic
• Spinal Cord : Analgesia – Either causes endogenous opioid release in substantial gelatinous – or inhibits release of Substance P – the jury is out currently.

Side Effects of Dexmedetomidine

Cardiovascular:

• Initial transient hypertension (peripheral α2B receptor activation)
• Subsequent hypotension and bradycardia (30% heart rate reduction)
• Decreased sympathetic outflow
• Cardiac output reduction (primarily rate-dependent)
• Dose-dependent catecholamine reduction (60-80%)

Respiratory:

• Minimal depression at clinical doses
• Mild increase in PaCO2
• Preserved respiratory drive
• Maintained airway reflexes

Central Nervous System:

• Cooperative sedation (easily arousable)
• Anxiolysis
• Analgesia/opioid-sparing effect
• Antiemetic properties
• Mimics stage 2/3 non-REM sleep

Other Systems:

• GI: Antisialagogue effect (dry mouth)
• Renal: ADH inhibition at collecting ducts (diuresis)

Uber Brief Neuroanatomy

The reticular activating system is built from four elements:

Locus Coeruleus	Upper Pons	Noradrenergic	Waking/arousal role
Raphe Nuclei	Midline Brainstem of pons, midbrain and medulla	Serotinergic	Pain/mood regulation/arousal /attention
Posterior Tuberomammillary Hypothalamus	Nr Hypothalamus	Histaminergic	Wakefullness/cognition/arousal
Pedunculopontine Tegmentum	Upper Pons	Cholinergic	shift from sleep to wake

RAS swings sleep from slow sleep rhythms (non-Rem/stage 3/’deep’ sleep) to fast sleep (REM)

This non-Rem stage is the state that shifts CSF around with pulsating vasoconstriction/dilatation in the brains of mice…. that might be the bit of sleep that tidies up brain debris.

Pharmacokinetics of Dexmedetomidine

Absorption & Bioavailability of Dexmedetomidine

• Intravenous : Bioavailability 100% : Onset 5-7 minutes (pronounced hypertensive response)
• Intranasal : 40%. : 45 minutes onset of peak
• Buccal : 81% Variable
• Oral : 16% Variable

Distribution of Dexmedetomidine

• Protein Binding : 94% (albumin & α1-glycoprotein)
• Volume of Distribution : 1.31-2.46 L/kg
• Steady State Vd : 118 liters
• pKa 7.1
• Distribution Half-life : 6 minutes
• Lipophilicity (Log P Octanol Water partition coefficient ) : 2.8

Drug Lipophillicity Segue….

Log Octanol/water partition coefficient (higher is more lipid soluble) (beaker of Octanol and Water 50:50 mix – see where the drug fancies going….)

As it’s a log, these are the orders of magnitude difference – of octanol vs water…. i.e. 2.8 orders of magnitude more dexmedetomidine in the octanol vs the water

Comparing Dexmedetomidine Lipid Solubility to other agents:

• Morphine 0.89
• Dexmedetomidine 2.8
• Fentanyl 4.05
• Propofol 4.33

Metabolism of Dexmedetomidine

• Primary Metabolism: Hepatic glucuronidation
• Secondary Metabolism: CYP2A6
• Hepatic Extraction Ratio: 0.7 (flow-dependent clearance)
• Metabolites: Inactive

Elimination of Dexmedetomidine

• Elimination: 95% renal, 5% fecal
• Elimination Half-life: 2 hours
• Clearance: 39 L/hour

Clinical Applications & Dosing of Dexmedetomidine

Standard Dosing Regimens

Preparing a syringe of Dexmedetomidine: Classically drawn up as 200mcg in a total of 50ml of either n.saline of 5% dex – 4mcg/ml concentration – if you’ve a programmed pump, Make sure the concentration is right!!!

PerioperativeHypnotic adjunct 1 mcg/kg over 10 min > 0.2-0.7 mcg/kg/hr. > Stop 5-10 min before end

ICU Sedation Avoid loading 0.5 mcg/kg/hr providing a smooth onset profile

Pediatric Premedication3 mcg/kg intranasal (Effect in 30-45 minutes)

Emergence Smoothing 0.3-0.5 mcg/kg/ Give slowly over 5-10 min during case

Preparation for 70kg adult:

• Standard concentration: 4 mcg/ml (200 mcg in 50ml)
• Loading dose: 70 mcg over 10 minutes
• Maintenance: 14-49 mcg/hour

Clinical Uses of Dexmedetomidine

1. Procedural Sedation
   • MRI sedation (especially pediatric)
   • Echocardiography in children
2. Neuroanesthesia
   • Awake-asleep-awake craniotomy
   • Cases requiring neurophysiological monitoring
   • Spine surgery with MEP/SSEP monitoring
3. Critical Care
   • Alternative to propofol (hypertriglyceridemia)
   • Facilitating ventilator weaning
   • Managing agitation and delirium
   • Alcohol/opioid withdrawal
4. Regional Anesthesia Enhancement
   • Block duration extension (IV administration prolongs block by ~3 hours)
   • Improved postoperative analgesia
5. Achieving a spontaneous breathing totally intravenous anaesthetic for Foreign body removal
   • A skill that is effective but not one to learn from the internet!

Safety Considerations

Contraindications

• Hypersensitivity
• Hypovolemia (will result in quite troublesome hypotension and potentially shock…)
• Diabetic autonomic neuropathy – might have challenging hypotension
• Hepatic impairment – Impaired clearance

Drug Interactions

• Enzyme Inducers: Increased clearance (carbamazepine, rifampicin, phenytoin)
• Glycopyrrolate: Paradoxical hypertensive response
• Other Sedatives: Synergistic effects requiring dose reduction…..

FRCA Primary Viva Questions

Question 1: Compare and contrast dexmedetomidine with propofol for ICU sedation.

Model Answer: Dexmedetomidine and propofol differ fundamentally in their mechanisms and clinical profiles. Dexmedetomidine acts via α2-receptor agonism, creating sedation with preserved respiratory drive and a sleep-like state that allows patient arousal. Propofol acts through GABA-A receptor potentiation, producing dose-dependent sedation to general anesthesia with respiratory depression.

Cardiovascularly, dexmedetomidine causes predictable bradycardia with hypotension, propofol also causes hypotension with maintained heart rate. Dexmedetomidine provides inherent analgesia, whereas propofol requires concurrent analgesia. Propofol has a more rapid onset/offset (elimination half-life 30-60 minutes versus 2 hours), but dexmedetomidine avoids propofol infusion syndrome risk. Cost considerations favor propofol, but dexmedetomidine may reduce overall ICU stay through improved patient cooperation.

Question 2: Describe the biphasic cardiovascular response to intravenous dexmedetomidine and its underlying mechanisms.

Model Answer: The biphasic cardiovascular response consists of initial hypertension followed by sustained hypotension with bradycardia. Initially, dexmedetomidine activates peripheral vascular α2B-receptors, causing vasoconstriction and transient hypertension lasting several minutes. This effect is more pronounced with rapid IV administration due to higher peak plasma concentrations.

Subsequently, central α2-receptor activation in the locus coeruleus and medullary vasomotor centers reduces sympathetic outflow. This causes vasodilation, decreased systemic vascular resistance, and hypotension. Concurrent reduction in heart rate (up to 30% from baseline) results from both decreased sympathetic tone and inherent vagal activity. The bradycardia contributes to reduced cardiac output, as stroke volume remains relatively preserved. This central sympatholytic effect predominates during maintenance infusion and persists into the recovery period.

Question 3: A patient receiving dexmedetomidine sedation for awake fiberoptic intubation develops significant bradycardia. Discuss your management approach and the pharmacological basis for treatment choices.

Model Answer: Management requires assessing the clinical significance of bradycardia while understanding dexmedetomidine’s unique pharmacology. First, evaluate hemodynamic stability – if the patient maintains adequate blood pressure and perfusion despite bradycardia, observation may suffice as this is an expected pharmacological effect.

If intervention is required, consider the underlying mechanism: reduced sympathetic outflow and enhanced vagal tone. Glycopyrrolate, while addressing vagal components, may cause paradoxical hypertension the mechanism is not entirely elucidated but may be due to increased CO from increased heart rate in an otherwise preserved stroke volume state.

Preferred options include reducing or stopping the dexmedetomidine infusion (effects wane within 5-10 minutes given the context-sensitive half-time). If immediate correction is needed, ephedrine provides both chronotropic and inotropic support through mixed adrenergic effects.

References and Resources

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

α2-Adrenoceptors in Pain Modulation: Which Subtype Should be Targeted? – Anesthesiology

Abdallah et al. – IV and Perineural Dexmedetomidine Similarly Prolong Regional Anesthesia – BJA

IV and Perineural Dexmedetomidine Similarly Prolong the Duration of Analgesia after Interscalene Brachial Plexus Block

Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep – Nature (MICE!)

Log Octanol:water Coefficients from a COSHH type databank

BJA Education: Dexmedetomidine in Paediatric Anaesthesia

BJA Education: Dexmedetomidine: its use in intensive care medicine and anaesthesia

Peck and Hill: Pharmacology for Anaesthesia and Intensive Care (Pages 267-268)

Neuroanatomy: Reticular Activating System Review

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Transcript

Gas Gas Gas Podcast Episode 42: Dexmedetomidine

Introduction and Welcome

[00:00-01:28]

Please listen carefully. Hello, and welcome to Gas, Gas, Gas. This is the best podcast for the FRCA primary exam. Our goal is to fill your brain with all this highly useful information. You might be in the gym right now, commuting, or ironing your scrubs. Regardless, the revision is eventually going to end, but for now expect facts, concepts, model answers and the odd tangent. Make sure to check out gasgasgas.uk. There’s show notes there, there’s loads more detail. Make sure to like and subscribe.

Anyway, buckle up, get ready for your mind to be bent into a new shape, and let’s get on with the show.

Hello, everyone, this is James at Gas Gas Gas. Today we are talking about dexmedetomidine. We’re going to talk pharmacodynamics, pharmacokinetics. There are a number of predetermined tangents we’re going to dip into, particularly the briefest moment on what the reticular activating system actually is in the brain. A bit of an exploration into how you might actually go about sticking a number to describe the lipid solubility of a drug or lipophilicity of a drug. And there’s one third little tangent, but I’m not going to tell you about that one just yet.

So if you’re enjoying the show, make sure to tell your mates, like, subscribe, do all those sorts of magical things. And if you feel like you’re really benefiting a lot from these episodes, think about chucking us a donation. But now for the delightful moment you’ve all been waiting for, and don’t worry, I’m going to tell you the molecular weight of dexmedetomidine shortly. We’re going to get on with the show.

Drug Basics and Presentation

[01:28-03:47]

So dexmedetomidine. Other names for this drug include Precedex, which is the brand name in the United States, and Dexdor, which is the brand name in the United Kingdom. It’s been in use in the United States since 1999 and it finally made it through the graceful doors of the United Kingdom in 2011. It’s an imidazole derivative. Lots of drugs are imidazole derivatives though, such as our dear friend etomidate. This behaves entirely differently to etomidate.

How is it presented? So it is a clear, colourless liquid presented in a hundred micrograms per mil. Classically, you get a two mil ampoule, so 200 micrograms. It is an enantiomer pure preparation, so it is the D-enantiomer, and the other half of the racemic mixture was inactive. The racemic mixture was called medetomidine, and I think it was mostly used in the veterinary side of things.

Brief side note here. We’ve called it the D enantiomer – Dex – dexmedetomidine, D being dextro. The opposite of dextro is levo, like levobupivacaine, and that’s with the polarised light approach to classifying enantiomers. However, it’s important to remember that there is another way of classifying enantiomers that we mentioned in that previous episode, which I’m sure you’ve listened to several times now, detailed notes taken, which is the Cahn-Ingold-Prelog method, where you end up with either a sinister or a rectus enantiomer. And this is the one, remember, where it takes the atomic numbering approach, whereby it goes from lowest to highest, and if that tracks around the molecule in a clockwise or counterclockwise manner, that’s how they name it. So, dexmedetomidine is also the S enantiomer as well as the D enantiomer. Drugs can be S and D or they could be S and L, they’re not exclusive.

If you’ve got your pens ready, I can tell you that the molecular weight of dexmedetomidine is 200.28 grams per mole. I add it there for completeness if anyone is asking. I don’t know. I mean, try not to look at the examiner with a withering look of absolute hatred and smile sweetly and say, not quite sure, perhaps 200, because most of them do seem to be hovering around the 200 mark. Then try and get them to move on, gloss over that bit.

Mechanism of Action

[03:47-07:57]

Mechanism of action: Dexmedetomidine is an alpha-2 receptor agonist. This seems to always fall out of my brain. I’m like, is it alpha-1? Is it alpha-2, does it antagonise? Does it agonise? I don’t really think there’s any magical way of remembering this. Alpha-2 receptor agonist.

Now, alpha-2, that means it’s going to work on G-protein coupled receptors. We know that the alpha receptors are Gi-linked, i.e., inhibitory, and we need to just remind ourselves that Gi subunits break off from the inner workings of that protein complex, and they totter off and inhibit adenylyl cyclase enzymes within the cell. This leads to less cyclic AMP, remembering that adenylyl cyclase converts ATP, adenosine triphosphate, to cyclic AMP, adenosine monophosphate. This lack of cyclic AMP leads to less inhibitory activity on potassium channel activity in that cell. That means you’ve got more open potassium channels. Potassium leaks out of the cell and the cell becomes more negative because you’re losing cations, positive ions. This impairs signalling.

So where do you find these alpha-2 receptors? Well, all over the body, folks. The ones we’re interested in are in the brain. As we all know, no drug is perfectly going to bind to just one singular receptor. They always get tempted. It’s always like, you know, you’re walking down the cereal aisle, you’re going straight for the porridge, but then you see the chocolate Weetabix minis and you’re like, ooh, I have less affinity for those, but I still do fancy them. So drugs get tempted elsewhere, but they have a preference. Dexmedetomidine prefers alpha-2 receptors.

Wouldn’t it be absolutely delightful if we could put a number on this? And the answer is yes we can, folks, because we can think about the ratio of affinity of dexmedetomidine to an alpha-2 receptor compared to perhaps an alpha-1 receptor. And when we’re making comparisons it’s always useful to compare to a different agent as well. So we’re going to compare it to clonidine. So if you had a gaggle of alpha-2 receptors and alpha-1 receptors available to your measure of dexmedetomidine and clonidine, the dexmedetomidine would preferentially go for the alpha-2 receptor one thousand six hundred and twenty times for every one time it was tempted towards an alpha-1 receptor. Clonidine, the ratio is 220 to 1, so you could approximate that dexmedetomidine is about eight times more interested in alpha-2 receptors versus alpha-1 receptors compared to clonidine. So it’s much, much more interested in alpha-2.

This bears a degree of relevance because at our sites of action, there are a number of sites of action for these alpha-2 agonist drugs. You also find alpha-1 receptors, and the alpha-1 receptor agonism actually causes contrary effects. So, clonidine almost inhibits itself slightly, at least according to Peck and Hill. Less of an issue with dexmedetomidine.

Now so we know what receptor it agonises, but where are these receptors? It seems that they’re all over the place, but the ones that perhaps play a more useful role in the effects we are looking for with dexmedetomidine is the locus coeruleus that’s found in the upper pons. That is involved in waking and arousal, and it releases noradrenaline normally. Locus coeruleus means blue spot, I imagine. If you were to slice into someone’s brain at the right height, you might find a blue bit. Dexmedetomidine also has activity in the ventrolateral preoptic nucleus, acts on other elements of the reticular activating system, and is also found to have a degree of activity in the spinal cord where it either, because no one’s really clear on this, increases the release of endogenous opioids or inhibits the release of endogenous nociceptive agents like substance P – substance pain, substance P. Doesn’t seem that clear.

The Reticular Activating System (Tangent)

[07:57-11:11]

Now, just very quickly, a brief dip into neuroanatomy here of the very briefest moment because it’s not in the exam, it’s just for interest. So feel free to, you know, daydream looking out the window or refill your iron as you know, obviously, you’re ironing your scrubs.

So, the reticular activating system. This gets bandied around. People say, oh, this and that, and arguably, who the heck knows what that is? So, it’s actually made up of four elements. The locus coeruleus is found in the reticular activating system, and as I said, involved in waking arousal and it’s noradrenaline releasing. You’ll also find the raphe nuclei. These are found in the midline of the brainstem at heights of midbrain, pons and medulla, involved in pain, mood regulation, arousal and attention, and that’s serotonergic. The third element of your reticular activating system is the posterior tuberomammillary hypothalamus, which is a mouthful. It’s histaminergic, involved in wakefulness, cognition, and arousal. And then finally, the pedunculopontine tegmentum, which is cholinergic and is involved in the shift from sleep to wake. I imagine most drugs that have sedating effects are probably messing about somewhere in here.

Now, what’s the role of the RAS overall? Well, sounds like it’s either going to be keeping you awake or enabling you to sleep. Generally speaking, if anyone asks – they won’t – the RAS is involved in swinging you from some different stages in sleep. I’m telling you this because dexmedetomidine creates a sleep-like state as opposed to a truly bonked on the head, anaesthetised hypnotic state.

So the RAS swings you normally from two rhythms in your sleep, stage three or slow wave sleep, sometimes called deep sleep, and then into fast sleep rhythms, REM sleep. Interestingly, the non-REM stage, this deep sleep, stage three sleep, is the state that seems to be involved in facilitating the flow of CSF around your brain. Now they’ve not really proved that in humans yet, but they have found it in mice. This CSF clearance system is called the glymphatic system, and there’s a postulation that this is involved in tidying up your brain.

Proven in mice, not proven in humans, but they interestingly found in this mice study – and the mice study is linked at the bottom of the show notes, or you could probably just search for glymphatic mice sleeping or something like that – is that when these mice were given zolpidem, which is a Z-drug like zopiclone, it inhibited this deep wave sleep. So actually, they didn’t get the restorative sleep that you might otherwise expect.

Now, I’m going out on a big limb here that I reckon ITU patients who are sedated on propofol don’t get any sleep. And they wake up bonkers because their brain is full of debris that they were meant to be neatly tidying away when they were in this delightful deep stage three phase that isn’t a big phase in your overall sleep cycle, but it’s important, and no tidying up gets done. Suddenly, they wake up and their brain is mad. Now, there’s no evidence for that. And I could be completely wrong, but I just feel that that makes logical sense. I’d love to see some science.

So that was my attempt at being uber brief with neuroanatomy. And I hope that you’ve now woken up and we’re going to actually think, what does it do when we give someone dexmedetomidine?

Clinical Effects and Applications

[11:11-14:16]

Well, it makes them less anxious. It has analgesic properties or opioid sparing properties. It can mitigate some of the side effects and symptoms of opioid withdrawal. And as we’ve mentioned, it sedates people. And it’s like a bit of a weird sedation, because they’re a bit dozy, sleepy. You can rouse them and prod them, and they’ll wake up and make sense and then doze off again, which makes it quite a useful drug.

So it can be used for dexmedetomidine-only sedation in MRI, chiefly for kiddies, echocardiograms in kiddies. It can be utilised perioperatively when you want to spare volatile or propofol. For example, when you need neurophysiology monitoring, maybe spines, etc. It’s used for awake-asleep-awake craniotomy. You can get them quite delightfully dozy on the dexmedetomidine, sneaking a bit of propofol here and there when you need it, like when you’re Mayfield pinning or when you’re squirting in stingy local anaesthetic.

I’ve seen it used for foreign body retrieval, where you carefully give someone dexmedetomidine over maybe five, ten minutes, get them quite dozy, and then very slowly creep up on the propofol and remifentanil. Very slowly. I’m not advocating you do this by yourselves, but it works really nicely. I’ve seen it, and it reduces your volatile requirements.

Dosing it, there’s lots of different doses. The classic regimen is you give someone a loading infusion of one microgram per kilo over ten minutes, and then you drop down the rate to 0.2 to 0.7 mics per kilo per hour. If you’re using it on intensive care because someone’s rattling or they’ve got hypertriglyceridaemia from too much propofol, it’s suggested that you don’t load the patient and you just start them at like 0.5 mics per kilo per hour and wait. It’ll take a while to reach steady state if you do that, but it’s a nice smooth take off.

If you’re doing the classic regimen, it probably takes five to seven minutes for a dose adjustment to look and demonstrate the effect you were hoping to achieve, worth stopping it about five to ten minutes before the end of a case for it to start tailing off.

It’s used to get kids down to the anaesthetic room in the UK with a dose that’s three mics per kilo intranasally. We’ll talk about the bioavailability when we get to the kinetics section. Three mics per kilo, squirt it up the nose. Half an hour, forty-five minutes later, dozy kid, who probably does have a lower blood pressure now – again in a minute. Off to theatre they go, waft some volatile at them without waking them up. Done.

Can also be utilised as sort of a one-off dose. 0.3 to 0.5 mics per kilo, given slowly, like in aliquots over five or ten minutes. Smooths out extubation, smooths out emergence. Obviously it has some analgesic properties, but does cause side effects, although obviously the smaller amount of drug you give, the less you see side effects. That’s sometimes utilised for tonsils and stuff.

Pharmacodynamics – System Effects

[14:16-17:17]

Okay, so pharmacodynamics. So we’ve almost crept our way through pharmacodynamics. One of the big elements here is the side effects. If you’re talking about side effects of a drug, structure it by system, start with either the cardiovascular system or you know the most relevant system with the most relevant side effect.

As you can expect with a hypnotic agent, it has cardiovascular system side effects. Etomidate being the outlier. In a fit, healthy patient, given dexmedetomidine, you will expect a drop in their mean arterial pressure and a drop in their cardiac output. What causes that? So their stroke volume is stable, but their heart rate drops by like up to thirty percent. But what do you see first? Well, actually you see first a paradoxical hypertensive state, especially with IV dosing. You don’t really see it quite so much with other dosing that leads to a lower peak plasma concentration. That’s because you agonise alpha receptors within the vasculature. And we know that noradrenaline, alpha agonist, increases your systemic vascular resistance, pushes your blood pressure up. You will get a responsive bradycardia to that as well.

But then you get hypotension. Now, why do you get hypotension? Well, there is a degree of sympathetic nervous system outflow modulation that comes from the reticular activating system. And when that is modulated with these drugs, you actually see less sympathetic outflow. And this is why you end up with a lower blood pressure and a lower heart rate, because your sympathetic nervous system is less jazzed up. This can be utilised because dexmedetomidine mitigates the sympathetic response to surgery and might also have some ischaemic protective properties as well, although I think that’s an area of research there.

So you’ve got a bradycardic patient you’ve just given dexmedetomidine to. Glycopyrrolate seems to cause a bit of a paradoxical hypertensive response if you’re trying to just treat the bradycardia. I think most folks just accept that the heart rate’s a bit slow. You could give metaraminol, doesn’t cross the blood brain barrier, cause a bit of squeeze, or you could reach for ephedrine. There is a dose dependent reduction in catecholamines, this has a sustained effect after, you know, after the patient’s awake and in recovery, they still have quite an obtunded sympathetic response to the world around them.

Respiratory effects. So generally speaking, in the doses we are using, it has minimal effects on the respiratory system. So it will keep people breathing. Now it might mildly decrease minute ventilation, and the PaCO2 of the patient might creep up slightly, but it’s not devastating.

We’ve mentioned CNS wise, you’ll see sedation and anxiolysis. There’s also a degree of antiemesis because of the effects dexmedetomidine has on dopamine in your locus coeruleus. I’ve come across a great new word here, which is psycholepsis or psycholeptics, which is just a fancy way of saying hypnotic drugs.

GI wise, it’s an antisialagogue, gives people a bit of a dry mouth, and from the renal side of things, it can inhibit anti-diuretic hormone at the collecting ducts, causing a diuresis.

So that’s pharmacodynamics done.

Pharmacokinetics

[17:17-21:02]

Now what about pharmacokinetics? Remembering this as absorption, distribution, metabolism and elimination. So routes of administration is probably the first thing to just briefly think about here. So you can give it orally – 16% oral bioavailability. You can give it nasally – 40% bioavailability, forty-five minutes or so to work. If you can somehow convince someone to swill it around their mouth for long enough, it’s got an 81% buccal bioavailability.

We mentioned it’s really quite lipid soluble. It crosses the placenta and the blood-brain barrier really easily. How is it distributed? So dexmedetomidine is 94% protein bound. It likes albumin and alpha-1 glycoprotein. No surprises there. Clonidine, as a comparator, is only 20% protein-bound, so the free fraction is much higher. Volume of distribution of dexmedetomidine 1.31 to 2.46 litres per kilo. Or if you’ve given someone an infusion and you’ve reached steady state, 118 litres volume of distribution. It’s got a distribution half-life of six minutes. It kind of gets where it needs to go quite nicely. Doesn’t take too long. It’s really lipophilic. Its pKa is 7.1, so it’s soluble in water. That’s why your infusions can be in saline or glucose.

I’m just breaking off here, how do we actually put a number on lipid solubility or lipophilicity of a drug? We’ve got something called the oil-gas partition coefficient for volatiles. Don’t really use that for this. We use something called the octanol-water partition coefficient. We’re going to use a log octanol-water partition coefficient. The higher the number, the more lipid soluble. We’re just going to quickly go through a couple of numbers here.

So how does dexmedetomidine stack up? So, dexmedetomidine, its log-octanol water partition coefficient is 2.8. So, that means there will be 2.8 orders of magnitude. So that’s not 2.8 times, that’s 2.8 orders of magnitude. And an order of magnitude is like ten to one hundred or one hundred to a thousand. So remember, we’re doing logs here. There’ll be 2.8 orders of magnitude more dexmedetomidine in the octanol within your beaker versus the water in your beaker. How does this stack up? So, fentanyl, it’s 4.05, and propofol is 4.33. So, fentanyl and propofol are more lipid-soluble than dexmedetomidine, but dexmedetomidine is still really quite lipid soluble. Morphine is 0.89, so you’ll have 0.89 of an order of magnitude more in the octanol versus the water in your beaker of water and octanol. So that actually makes quite a lot of sense when you think about it.

You’re trying to study for the FRCA primary exam and your brain is probably melting. It’s probably trickling out of your ears as we speak. It’s going to get better. You’re going to know loads of stuff. It’s going to be really cool. So just keep gently plugging away at it. Don’t lose your mind.

Metabolism of dexmedetomidine. It seems there’s a few different routes that dexmedetomidine can take, but ultimately the end point is inactive metabolites. Mostly it’s getting glucuronidated, but there is some cytochrome 2A6 action. Patients on enzyme inducers, as you might expect, can speed up clearance of dexmedetomidine, and dexmedetomidine has a reasonably high extraction ratio, so therefore, more cardiac output equals more liver clearance of dexmedetomidine.

Where do these inactive metabolites go? Well, almost entirely in the urine, 95%, and a little comes out in the poo via bile. Elimination half-life, two hours, clearance thirty-nine litres per hour, although that’s not indexed to body mass, which is kind of unhelpful, isn’t it?

Special Considerations and Clinical Pearls

[21:02-23:50]

Other things to note. If someone’s got a significant hepatic impairment, don’t give them as much drug. Old folk clear dexmedetomidine at similar rates to the young, but remember old folk are more sensitive to the drug. So you can have the same amount of drug in Mrs Miggins and eighteen year old Charlie, but Mrs Miggins is going to be flat as a pancake because she’s more sensitive. So, you don’t need to use as much.

An important note: hypovolaemic patients do not like dexmedetomidine. You will tank their blood pressure and it will be a mess. Dexmedetomidine can also unmask patients with orthostatic hypotension quite dramatically, and your kiddies and your adults post-op on dexmedetomidine are more likely to have a postural drop because remember we’ve just inhibited their sympathetic nervous system. As you can imagine, other patients with slightly sketchy sympathetic nervous systems probably don’t fare quite so well with dexmedetomidine either. These are your diabetics with neuropathy and your chronically uncontrolled hypertensive patients.

Now, you could make a good argument here that as we develop more experience with dexmedetomidine, we might actually realise that, well, propofol is not very good for hypovolaemic patients either, is it? We shouldn’t get too snarled up on this sort of stuff, but it’s, you know, when you’re venturing off into drugs unknown, those positions are harder to defend.

And just harking back to our perineural local anaesthetic episode, we know dexmedetomidine seems to be a great choice for bolstering our regional anaesthesia. There’s a paper Abdullah et al., but the crux of it is: perineural dexmedetomidine versus IV dexmedetomidine versus placebo. What does it do to the block? So if you stick it next to the nerve, the block lasts 10.9 hours. If you give it IV, 9.8 hours. And if you don’t give the patient any dexmedetomidine at all, 6.7 hours. I’ll link to those in the show notes. IV dexmedetomidine, prolongs your block. Dexamethasone, IV, prolongs your block. So why not give them a little bit?

And I don’t know what doses they used, but I imagine that a delightfully dexmedetomidine patient who’s having ankle surgery under a block or maybe shoulder surgery with a tickle of dexmedetomidine when it keeps them breathing might be quite pleasant. We just need to think, does it – do these drugs keep patients in PACU longer? I’ve seen old folks who’ve been given clonidine spend ages dozing off in recovery. The likely answer is yes, they take longer in PACU.

Now you would hope that that’s because actually the evidence would also suggest, well yeah, they have less emergence delirium and they’re easier to look after in recovery because, you know, they’re more analgesic, etc. From an evidential perspective, that doesn’t seem to play out. But an N of 5 conversation with some recovery nurses at a local tertiary paediatric centre for the dexmedetomidine tonsils versus the non-dexmedetomidine tonsils – they preferred the dexmedetomidine tonsils because they took longer to wake up. So they were less challenging to recover. Don’t know how great that is for theatre throughput though.

Closing Thoughts

[23:50-24:51]

So check out the show notes for more detail here, guys. There’s a few bits and pieces on drawing up, mixing, a bit of conversation more about what doses to give and when you might do that, and obviously all the links to the papers that exist for talking about dexmedetomidine and ITU, dexmedetomidine and paediatrics, pharmacodynamics and pharmacokinetics of dexmedetomidine, that paper about the glymphatic flow in mice and how it might influence brain tidying up, and how that could relate to our ITU patients not actually sleeping for two weeks. Poor things.

Hope you have a nice weekend. See you next week. We’ll probably do clonidine just to tidy things up. See you then.

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