Ep 14 – Ketamine for the FRCA

Introduction and Podcast Overview

00:00-00:58

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Hello, my fellow Gas Gas collaborators. This is James from Gas Gas Gas and today we are talking everything you need to know about ketamine for the primary FRCA exam. We’re going to look at its properties, its clinical uses, and spend some time on the NMDA receptor and what that gets up to. We’re going to pile straight into some questions, because I think that’s probably the best way to cover this.

The NMDA Receptor: Structure and Function

00:59-03:23

Doctor, tell me about the NMDA receptor and its function in the human body.

Oh, yes, the NMDA receptor found throughout the brain and spinal cord. It is a transmembrane receptor made up of NR1 and NR2 subunits, and it is an ion channel, mostly for calcium, but other cations can transit it either in or out of a neuron. It has a number of additional binding sites which allosterically modulate its action.

Glutamate, NMDA, glycine, and a number of others are suggested to bind to it. Oh, I’ve just remembered I should have defined NMDA, shouldn’t I? Sorry, Examiner. NMDA stands for N-methyl-D-aspartate receptor.

This receptor is found on neurons. Even when it’s in its open state, if a number of these allosteric modulators have bound and conformationally changed it to be open, it is often obstructed by magnesium in a non-depolarised neuron, i.e. one in its resting state. This magnesium obstructs the flow of cations. Therefore it means that this obstructive magnesium ion is actually critical to the functional nature of this receptor.

In the resting state the neuron is relatively electronegative, and the positivity of a magnesium cation means that it sits quite merrily in this pore. It is only displaced when the neuron itself depolarises due to it receiving an action potential sufficient to trigger depolarisation.

When it meets these criteria and the pore is in fact open and unobstructed, calcium influx is the chief cation that shifts. However, sodium can also influx through this pore, and potassium can escape from the intracellular environment. The calcium influx is considered the probable mechanism by which the NMDA receptor mediates its physiological function.

These are neuronal plasticity, learning, and memory formation. It is also involved in the modulation of pain. Downstream effects of this calcium influx, which I’d be surprised you’re getting to if the examiners let you talk this far, is nitric oxide synthetase inducing nociception can cause neurotoxicity in significant amounts and is probably involved in some of that central pain sensitisation.

Hopefully the examiner has jumped in well before now and poses another question.

NMDA Receptor Antagonists

03:23-03:35

Ah, well, that’s all well and good. What drugs can you think of that interact with this NMDA receptor?

The chief drug that comes to mind here is ketamine.

Yes, yes. Tell me more about ketamine, please.

Ketamine: Presentation and Dosing

03:35-04:43

So ketamine is a phencyclidine derivative. It is presented as a clear colourless liquid in a racemic mix of S and R ketamine, often provided either in solution at fifty milligrams per mil, or ampoules of one hundred to two hundred and fifty, or five hundred milligrams, as a powder that needs to be reconstituted in saline.

Of note, regarding the racemic mix, S-ketamine is two to four times as potent as R-ketamine and generally has a more favourable side effect profile.

The dosing route for ketamine is chiefly IV or IM, although there is an oral preparation too. Dose-wise, depends on your end goal, be that anaesthesia or sedation or analgesia. IV general anaesthesia is achieved with a range of either 0.5 to 2 milligrams per kilo, depending on your patient and their clinical state. Onset time for that is thirty to ninety seconds, lasting for five to ten minutes.

For the sake of time, I’ll be nice and succinct with the doses. An IV analgesic dose is 0.1 to 0.5 milligrams per kilo. The IM doses are higher.

Pharmacodynamics and Mechanism of Action

04:43-05:22

So from a pharmacodynamics perspective, its mechanism is actually multiple. Chiefly, it is a non-competitive NMDA receptor antagonist, but it also has activity at the opioid receptor, the muscarinic receptors, and sodium channels on neurons. It generally produces a dissociated anaesthetic due to disconnect between thalamus and cortex.

From a side effects perspective, cardiovascularly considered very stable, causing an increase in heart rate and blood pressure, mediated by inhibiting neuronal uptake of catecholamines in the sympathetic nervous system. It does have a direct myocardial depressant effect, though.

Respiratory and Other Effects

05:22-06:01

Ketamine preserves airway reflexes and maintains airway patency, significantly more so than other general anaesthetic agents. It increases respiratory rate, is a bronchodilator, but does cause hypersalivation. It’s also noted to reduce pulmonary vascular resistance.

It can increase intraocular pressure. Its other neuro effects include an increase in cerebral blood flow and intracranial pressure. However, this is not significant in the context of head injury generally.

It has a significant neurological side effect of emergence delirium, which can be significantly distressing for patients. That can be mitigated with midazolam.

Pharmacokinetics

06:01-06:47

From a kinetics perspective, its oral bioavailability is poor, at around seventeen percent. Its volume of distribution is three litres, and it is twenty percent protein bound, which is the least of the hypnotic agents. Its pKa is 7.5. Its unionised fraction is perhaps sixty percent.

It is metabolised in the liver by N-demethylation producing norketamine, which has about thirty percent of the activity of ketamine. This is subsequently either hydroxylated or conjugated into water soluble molecules that are cleared renally.

Its clearance is seventeen mils per kilo per minute, and it has a distribution half-life of around eleven minutes, 2.5 hours for a clearance half-life. For plasma, so it redistributes really quickly.

Processed EEG Effects

06:47-07:24

And what happens to a processed EEG if you administer ketamine?

If they’re asking you these sorts of questions, it’s probably to kill time. The processed EEG, when you give ketamine, goes nuts. You probably need to frame it along the lines of, for example, BIS index monitoring - your BIS number will go up. This isn’t that the patient is more aware, it is a reflection of the disordered neuronal activity that’s leading to the algorithm interpreting that as consciousness or an increased level of alertness, probably a better word to use.

Understanding Enantiomers

07:24-08:28

So we’ve talked quite a bit there about the properties of ketamine. I just wanted to touch on enantiomers, mainly because I always forget about enantiomers, so I’ve decided to break down the word enantiomer for you using the wonders of the internet because I did not do classics.

So, enantios in Greek means opposite and meros means part, so opposite parts. And this refers to the fact that an enantiomer is the same molecular makeup, i.e. the same molecules, but in a differing position that differs around a fixed chiral centre.

What they found is if they divvied up these racemic mixtures into their component two halves and then shined polarised light at them, it would rotate that polarised light in a particular manner depending on which half you are shining it through. And that’s what we’re talking about when we’re saying S-ketamine or R-ketamine or levobupivacaine.

Other drugs that are like this: bupivacaine, etomidate, tramadol.

Clinical Uses

08:28-09:43

Now on to the practical side of things. Where do we actually use ketamine? Generally, ITU flavoured RSIs and laparotomy flavoured RSIs, and you would be well justified in reaching for it in your patient with an expanding intracranial lesion, needing a nice thoughtful anaesthetic that doesn’t cause hypotension.

The important thing to bear in mind here is that it does drop blood pressure if your patient is incredibly clapped out, because the mechanism by which that increase in blood pressure is mediated is driven by inhibiting reuptake of catecholamines in your sympathetic nervous system. But if someone’s literally tipped off the cliff with a systolic of sixty or seventy, they don’t have much in the way of catecholamines left, so you give the drug a dose you think is right, and actually all you cause is myocardial depression.

Anecdotally, but there’s also a paper on it, doses down to 0.25 milligrams per kilo IV for induction have been used.

Its other chief use is sedation in recovery to pull bones and joints into better alignment. And also you can reach for it in your severely bronchospastic patient. Hopefully they’re already on ITU and hopefully they’re intubated because it’s a nice bronchodilator.

Severe Asthma and Emergency Use

09:43-10:13

And if you’re thinking that you’re in that fifty percent, twenty percent life-threatening asthma and you’re going to intubate them situation, which is terrifying, it’s probably a good choice there as well. It does cause hypersalivation though. Bear that in mind.

A use that doesn’t see much action in ITU, but I think A&Es have a tendency, is the “you’ve been a fairly naughty boy and you’re going to have some sedation now, whether or not you like it” because you’ve got nasal IV access. Here’s some ketamine IM.

Clinical Experience and Anecdote

10:13-11:07

My experience of ketamine is the onset does seem to be quite rapid in very sick people. They get glazed over, they might make an odd sound or say a couple of words, and then space out.

But I have seen, entertainingly and interestingly, a professor who had snapped his femur walking along some slightly slippery coastline doing some professorial stuff describe an out-of-body experience in A&E recovery when we were using ketamine to straighten out his leg. He was describing seeing us from above, being like, “oh, that looks wonky,” and then went, “ow,” when we pulled his leg. However, then he said, “oh, oh, actually, that didn’t hurt. Oh, how very strange.”

It’s very curious as to what sort of plane of anaesthesia or sedation he was in to explain these things to us. But I imagine his slightly scientific mind was trying to make sense of the situation and was exploring it. It was very interesting. Anyway, getting carried away.

Summary and Conclusion

11:07-11:55

In summary, it’s an ace drug, especially if you’re not going to be waking the patient up because you dodge the emergence delirium. The reason why it’s not used as a routine agent is because of that delirium. Pairs really nicely with rocuronium.

The next episode is going to be a bit more parochial, and we’re going to explore morphine in a similar manner. So, my name’s James, and you’ve been listening to Gas, Gas, Gas. Thank you very much.

If you found it useful or awful, please like and subscribe and rate the show. Definitely check out the show notes for those diagrams and the detail of this content. It is a bucket of content to get to grips with. Keep working at it and you will get better, faster and stronger. It is vital to keep your interest alive for the science that we’re covering and not overcook yourself. You will be amazed by what you know come exam day. Don’t freak out, keep studying.