Ep.22 – Alfentanil for the FRCA Primary

Introduction and Episode Overview

00:00-01:48

Please listen carefully. Hello everyone, this is James at Gas, Gas, Gas, and today we’re doing drugs, particularly alfentanil.

We’re harking back a little bit to the earlier days of Gas, Gas, Gas, having finished off our run of VivaCast episodes for now, and we’re working our way through that back catalogue of all the drugs in your anaesthetic armamentarium or the cupboard of good stuff. I like to tell patients that if they have any problems I have a humongous cupboard of all sorts of medicines to solve problems and that it’ll all be okay. And it is – we do have an absolute pharmacopoeia at our fingertips with which to utilise effectively. But we’ve got to make the right choices and to make those right choices, we need to know about the damn drugs. And that’s why we’re doing this.

Anyway, before I get into the nitty-gritty details of all the numerics of alfentanil, which is important to have an appreciation of, if not a verbatim, can vomit the data out, memory situation – that’s a bit excessive. Unless, of course, you’re studying for this exam.

Anywho, so where did alfentanil come from?

Historical Development of Opioid Drugs

01:48-04:47

Summary: The evolutionary pathway from pethidine to fentanyl and its analogues, including the discovery of alfentanil.

Well, as you can imagine, we have to go on a journey through time. And it starts with pethidine. This can also be called pethidine in the UK, and I think Demerol in other corners of the world.

And pethidine was discovered in 1938, whilst actually they were looking for powerful anticholinergic drugs to treat asthma, I believe. It was discovered by a chap called Otto Eisleb – forgive me if I can’t pronounce that name right – in Germany.

But whilst they were testing it, they realised that it was an opioid receptor agonist, and thought, “well actually, whilst it doesn’t seem to be a very good anticholinergic, it’s great for pain, let’s use it for that.”

And you know, like morphine, we all have probably heard that pethidine sort of maybe treats pain, might stop post-operative shivering, but no one really uses it anymore. At least in UK practice. But it was a precursor to many other potential drugs.

Paul Janssen and the Development of Fentanyl

And there was a gentleman called Paul Janssen who decided to start fiddling around with the pethidine, noting that it was more lipid soluble than morphine and wanted to figure out if he could make it any better.

So they started adding bits and pieces to it and I’m not going to pretend like I have any idea about organic chemistry here. But ultimately, in 1959, fentanyl was discovered.

There was an interim molecule that Janssen discovered to be about 20 times more potent than morphine called phenoperidine, labelled by them. To make phenoperidine into fentanyl, they plonked a bit of an extra carbon chain in the backbone between some other bits. Very, very clever.

But interestingly, if you take fentanyl and add a carbon-oxygen-carbon tail, you create carfentanil. And you might have heard of carfentanil, you might not. But ultimately, it is one of the most potent opioid receptor agonists known to mankind. It’s 10,000 times as potent as morphine.

And I’ll try and find the news article I read about it in the news years ago because someone had found a pallet of carfentanil, I think, in a basement somewhere in Canada. And it was enough to basically cause an opioid overdose in everyone within many, many, many, many, many square miles. But that might not be saying much if the population density was quite low. Anyway, there’ll be a link to that in the show notes if I can find it. I think they do use it for like anaesthetising elephants.

Neuroleptanaesthesia and High-Dose Opioids

Anyway, all these fiddlings going on with trying to discover better opioid receptors was coincident with attempts at the time to try and achieve what they were calling artificial sleep or twilight sleep, which was neuroleptanalgesia slash neuroleptanaesthesia, where they were using droperidol in high doses and opioids in high doses to achieve anaesthesia without gases, etc.

And whilst it sort of works with opioids, actually it worked really quite nicely with fentanyl.

High-Dose Morphine and Fentanyl Studies

04:59-06:09

Summary: Clinical studies demonstrating the use of massive doses of opioids as sole anaesthetic agents.

We’re going to move a little bit further forward in time now and just think a little bit more about morphine as a sole anaesthetic agent. And you’re aghast, I’m sure. “Morphine as the sole anaesthetic agent?”

Well, in 1969, Lowenstein and Powell studied the cardiovascular response to large doses of intravenous morphine in man, New England Journal of Medicine, 1969. And you kind of think, “what could be a large dose?”

I’m going to give you a moment to try and guess what that large dose might be before I put you out of your misery and say: one, two, three milligrams per kilogram.

And they noted that this was quite a useful agent in cardiac anaesthesia. It was very cardiostable. Unfortunately, it was unpredictably efficacious when it came to amnesia. And that probably means that it’s not terribly good, as we can all agree.

However, when they tried similar japes with fentanyl, it worked pretty good, demonstrating yet again quite a robust cardiac safety profile in doses of up to 100 micrograms per kilogram.

If we had all those tiddly little fentanyl ampoules, we would get through several boxes. But it does come in bigger ampoules, guys, and that’s great.

Anyway, this isn’t a podcast about fentanyl. This is a podcast about alfentanil. And that was discovered in 1976 at Janssen Pharmaceuticals.

Alfentanil Basic Properties

06:09-08:51

Summary: Introduction to alfentanil’s basic pharmacological properties and therapeutic index.

So alfentanil is 25% of the potency of fentanyl. It has a therapeutic index of 1080 in rats. And it’s short-acting.

And interestingly, guys, in monstrously massive overdoses – and like, you know, again, we’re drawing up several hundred ampoules here – if you give more than 5 milligrams per kilogram, it has a cardiostimulatory effect. It must clearly start binding to some other receptors when it’s floating around in extraordinarily large amounts.

I mean, 5 milligrams per kilogram – five ampoules drawn up for every kilo of the patient. 70 kilo patient, you’d be there all day, but they wouldn’t drop their blood pressure.

Therapeutic Index Explanation

Anyway, I’ve introduced something there called therapeutic index. I just want to touch on it to make sure that we’re all on the same page, because it would be daft to assume that everyone knows everything.

So therapeutic index is the division of the LD50 over the ED50. What are those?

• LD50: lethal dose, that would be sufficient to kill 50% of a test population
• ED50: the effective dose in 50% of that population

And really, what this tells you is that if you divide the lethal dose by the effective dose, if that’s a nice high ratio, it means that actually it’s quite hard to get it terribly wrong and kill someone with the drug.

It doesn’t mean that you might end up with a load of side effects and a really dozy patient for hours and hours and hours and hours and hours on end, but it hasn’t been lethal. And that’s an important thing.

Alternative Therapeutic Index: TD50

Now, but there’s also, guys, another therapeutic index that sometimes intermittently gets used interchangeably and is probably something just to be aware of and probably helps us weigh up what these things really mean.

Because we all know that some drugs have side effects that aren’t lethal but are irritating or side effects that we would classify as a toxic effect of that drug. We might think itching’s bothersome but not lethal, but respiratory depression can be lethal.

And this is called the TD50 – i.e. the toxic dose for a defined toxicity that you’ve planned and thought about beforehand of a drug in 50% of the test population.

And then some places index their therapeutic index to this as opposed to the lethal dose, which seems reasonable. It might help you weigh up the toxicity of, you know, choosing a morphine PCA over a fentanyl PCA in your hospital.

So it’s important to make sure that you know what number you’re using when thinking about therapeutic index in any agent, really, and what the actual definition of toxicity was for that named therapeutic index.

Clinical Perspective on Lethality

09:00-10:10

Summary: Discussion of how anaesthetists can manage theoretical “lethal” doses through airway management.

Anyway, we’re meant to be talking about alfentanil, but pharmacology is broad.

Now, the interesting caveat for us as anaesthetists is: how would you define this as lethal? In these test populations, you know, if the rat stops breathing, then I think we probably consider that lethal. But if we were to give a large dose of morphine and rendered a patient unable to breathe, well, we can sort that out as anaesthetists. Interesting conundrum.

Anyway, just so we’re all on the same page, and this is going to be in the show notes, and I’m going to include in the show notes a table of these therapeutic indices, etc., as best I can so we can try and at least put a bit of a pin on it, bearing in mind that studies are different, they have a different endpoint, they have a different definition of something which means that the number is different, so you can only really quote a range and it’s better to have an approximate idea than decide to pin yourself to the wall on a single number because the person you’re talking to might have a different number in their head. You look better if you say “well there’s a range here depending on how you interpret this, approximately this.”

Alfentanil Pharmacology Details

10:10-12:54

Summary: Comprehensive coverage of alfentanil’s formulation, mechanism of action, and pharmacokinetic properties.

Right, so now we’ve learned a little bit about where these agents come from, we’re going to talk very particularly about alfentanil.

Formulation and Availability

So alfentanil is available as a clear colourless solution in the concentrations of 500 micrograms per millilitre or 5 milligrams per millilitre. And you’re saying, “whoa, that’s a big dose.”

Let’s bear in mind that alfentanil isn’t just a bolus agent. It can be used as an infusion on intensive care. And if you’re expecting 20 ITU nurses to be drawing up 20 syringes of alfentanil for sedation maintenance using tiddly tiny ampoules, the odds of someone slashing their thumb cracking 20 ampoules is high.

Its molecular weight is 416 for all those excited people.

Mechanism of Action

And its mechanism of action: it is an opioid receptor agonist. It is highly selective for the mu-opioid receptor.

30 second touch on opioid receptors again. These are G-protein coupled receptors. They are bound with a Gi subunit on the intracellular side of this G-protein coupled receptor complex. It triggers downstream effects when it’s agonised of hyperpolarising cell membranes by increased potassium conductance – makes it harder to transmit a signal. Adenylyl cyclase inhibition, which reduces the levels of cyclic AMP within your cell, and this subsequently leads to more voltage-gated calcium channels closing. The sum effect is that it’s harder to transmit a signal.

pKa and Onset Properties

Moving on, what’s the pKa, you ask, of alfentanil? Well, it’s 6.5 and it is 89% unionised at a pH of 7.4, so there’s a humongous fraction of alfentanil ready to dive across those membranes into spaces filled with opioid receptors to do their wicked work and impair that signalling of pain.

Noting guys here that it has a lower pKa than fentanyl at 8.4. Fentanyl works very well because it’s massively lipid soluble in its biochemical makeup. So despite alfentanil having a lower lipid solubility than fentanyl, this is more than made up for in the unionised fraction and we would consider the onset of alfentanil to be faster than fentanyl. It seems to sort of kick in within a minute, maybe 90 seconds, whereas for full onset you’re thinking about three to five minutes for fentanyl.

Clinical Uses and Dosing

12:54-14:58

Summary: Practical applications of alfentanil in different clinical scenarios with specific dosing recommendations.

Clinical Applications

What can you use alfentanil for? Well we’ve spoken about using it as pain relief and sedation management in ITU. It’s a co-induction agent classically used in modified RSIs. Its onset time’s pretty great so you’re only going to be suppressing that patient’s drive to breathe for a shorter time compared to fentanyl.

It does a great job of obtunding the hypertensive response to laryngoscopy, much like fentanyl would, but it doesn’t hang around for as long as fentanyl, so it’s quite useful when you’re not doing a cardiac anaesthetic.

For example, if you’re having to do a crash section for an eclamptic pregnant lady needing a GA, a whacking dose of alfentanil is going to stop them having a systolic of 300 whilst you’re intubating them, and that does reduce your chances of stroke and that’s nice.

Pharmacokinetic Properties

It’s got an elimination half-life of 90 to 111 minutes and it has a lower volume of distribution compared to fentanyl. So the volume of distribution for alfentanil is quoted as 0.4 to 1.1 litres per kilogram whereas the volume of distribution for fentanyl as we’re revising here is 0.88 to 4.4 litres per kilogram.

So alfentanil doesn’t spread as much in a human, so to speak. We would consider it to be 10 to 20 times the potency of morphine. So you can imagine a 100 microgram dose is equivalent to about a milligram of morphine but it works far quicker than morphine.

Obstetric Use Example

So I reach for alfentanil in a section classically. If they’re still getting some stimulus at the end of surgery, if that spinal’s starting to wear off and they’re sewing up or if they’re struggling to cope with the unpleasant sensations that you cannot abolish with a spinal during a caesarean section, you can say, “I’ve got a drug that’s really going to help you here,” and give them a good dose, like 200-300 micrograms of alfentanil, reassuring them that they’re going to feel better, and they will get an overwhelmingly positive feeling. And you maintain control, and you maintain their trust, and you demonstrate that you’re taking their discomfort seriously. Great drug.

Dosing Guidelines

So what are the doses? So if you want to try and keep someone breathing, probably don’t give them more than 500 micrograms.

If your goal is to fully obtund that laryngeal response to intubation leading to hypertension, then you need to be giving 30 to 50 micrograms per kilogram.

Classic ITU infusion rates could either be 2 to 4 millilitres an hour of neat alfentanil – i.e. 500 micrograms per millilitre – or sometimes it’s dosed as micrograms per kilogram per minute, like up to 0.5 or so.

Obviously intubated patients on ITU can have plenty of alfentanil. It’s not really going to cause much bother.

Side Effect Profile

15:16-16:27

Summary: Comprehensive overview of alfentanil’s side effects across different organ systems.

Speaking about bother that alfentanil causes, what is its side effect profile you ask? Well, quite limited actually. It behaves itself very well, does alfentanil.

Cardiovascular Effects

It has cardiovascular effects though. It can mediate a vagal bradycardia, but that doesn’t seem to bear out in alterations, particularly in cardiac output. Systemic vascular resistance doesn’t alter your mean arterial pressure and nor apparently does it mess with your pulmonary capillary wedge pressure.

Respiratory Effects

As you could expect from a respiratory perspective, it’s a potent respiratory depressant and it has been implicated in wooden chest phenomenon. There’s a grumbling suggestion that the physiological basis for this is mu-opioid receptor agonism of GABAergic interneurons within your spinal cord. But who knows?

Other Effects

It can cause, from a GI perspective, sphincter of Oddi spasm. And looking at your eyeballs, it drops your intraocular pressure.

And unlike morphine, it does not increase your anti-diuretic hormone activity – i.e. it doesn’t cause you to hold on to water, which is probably actually something we should think about a bit more in our post-op patients. We’re giving them morphine because it’s convenient, everyone’s happy, but actually really, is it the best drug? Who knows?

Pharmacokinetics and Drug Interactions

16:27-17:39

Summary: Detailed breakdown of alfentanil’s distribution, metabolism, and potential drug interactions.

Distribution

So how is alfentanil distributed? So it’s heavily protein bound, 85 to 92% protein bound, and it seems to preferentially like the alpha-1 acid glycoproteins you find in the plasma.

It has a context-sensitive half-time at three hours of infusion of 47 minutes ± 12 minutes. Just so we’re all in the right frame of reference here, remifentanil has a context-sensitive half-time at three hours of 3.2 minutes ± 0.9 minutes. So a fair difference.

Metabolism

Metabolism-wise, the liver kindly does most of the work here and converts it via N-dealkylation to noralfentanil. Remember, fentanyl is converted to norfentanil mostly. This noralfentanil, which has undergone phase one metabolism, then undergoes phase two and is conjugated with glucuronide. And the cytochromes 3A4 and 3A3 are chiefly involved.

And now we all know, 3A4, I recognise that number. I should say alphanumerical. Therefore, you can imagine that things that mess with 3A4 might alter your alfentanil metabolism.

Drug Interactions

So clearance of alfentanil is prolonged by:

• Erythromycin
• Cimetidine
• Ketoconazole
• Fluconazole
• Ritonavir
• Diltiazem
• Midazolam

So if we’re putting our ITU hats on or our anaesthetic hats on, if you give someone an induction dose of midazolam plus alfentanil, you’re going to prolong your clearance a little bit. Probably not going to influence your anaesthetic overall though.

But if you’re on ITU and you’ve got a really sick patient and they’ve got ileus, so you’ve been giving them erythromycin and, you know, they have a belly full of candida, so they’re on fluconazole or something and then you know they were an alcoholic so actually they’re on a midazolam infusion too, then you might actually start seeing an accumulation of alfentanil and it takes longer to wear off.

Elimination and Clearance

17:39-20:14

Summary: Final pharmacokinetic parameters and practical clinical applications.

Elimination

And elimination, last but not least: so under 1% of alfentanil is excreted in the urine unchanged, but all the metabolites that bear out from its clearance in the liver are renally cleared. The extraction ratio is 0.3 to 0.5 and we would quote the clearance as 3.3 to 8.3 millilitres per kilogram per minute.

Clinical Applications Summary

That’s a lot of talking words isn’t it guys? Anyway, what should you use alfentanil for? What do I use alfentanil for?

I use it as an induction agent in RSI at reasonable doses. I’ll give them a milligram, maybe a milligram and a half if they’re very poorly to try and spare using other agents.

I use it for managing acute pain or acute discomfort in an obstetrics perspective. Obviously it’s used as boluses on ITU for managing intervention on ITU as required. In ITU it probably behaves a little bit differently because patients are going to get quite saturated after a few days so a little bit of a bolus goes quite a long way.

In some settings, other hospitals combine morphine and alfentanil and use it as a pain recovery protocol because we all know morphine takes ages to really work and alfentanil does not, so you can acutely treat that spike in pain, reassure a patient that you’re actually going to do something about it and wait for the morphine to start kicking in later. I think they call it “alfine” or something. Have a read, I’ll see if there’s a paper or something else to get in the show notes. I couldn’t tell you if it is licensed to do that, but again, sounds like someone’s being thoughtful and clever with drugs based on the science and pharmacology of said drugs. Whoever knew?

Conclusion and Next Episode Preview

20:14-20:57

I hope you enjoyed that trip down Alfentanil Lane. I think next episode I’m going to hit up etomidate just for a bit of a laugh. I’ve only used it once, it just took really long to work, but the patient definitely didn’t drop their blood pressure.

Anyway, cheers for listening guys, thank you very much and see you next time. Don’t forget to like, subscribe and tell your mates.

Thanks for listening guys. I hope you found it useful but if you found it awful do let me know. Please like and subscribe, register with whichever podcast platform you find yourself using and leave a comment if you think I need to square something away. I just want to make sure that you guys know that every day you are getting better at this. There is a bucket of content to try and consume and it is like drinking from a fire hose. Take it day by day, don’t overcook yourself, don’t freak out and keep studying.

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