Ep 3 – Fentanyl For The FRCA Primary

We're talking the core fentanyl waffle, and a jump into the opiate GPCRs. Closing up with some talk on using fentanyl in day to day practice.

Very commonly used opiate, chief uses include as a co-induction agent for anaesthesia, perioperative pain control, post op pain control and as an element of sedation for procedures / on intensive care. It is sometimes used in resus, but sadly not as much as it perhaps should!

Onset time is faster than morphine, with a side effect profile that may be better with fewer episodes of nausea due to its higher selectivity for the mu opiate receptor.

The Opiate Receptors and Classes - MOP, DOP, NOP, KOP?

Are All G-Protein Coupled Receptors (GPCRs)

When a ligand, binds to the receptor site on the Opiate G-protein coupled receptor, ( We know there are endogenous versions of things that bind to that, i.e. endorphins, encephalins, these things called dianorphins,) It triggers a secondary messenger system within the cell.

Overall this mediates effects within a neuronal system leading to altered/impaired depolarisation of pre-synaptic membranes and hyper polarised post synaptic membranes

1. So you bind your ligand to your G-protein coupled receptor. (opiates bind to them, but also remember naloxone also binds to these receptors.)
2. The GPCR undergoes conformational change across the cell membrane.
   • Remember these GPCRs are transmembrane, and they have seven transmembrane crossing points described as being serpiginous. (I'm sure you remember all that from medical school.)
3. Gi G-protein is released, and this has down stream intracellular effects
4. Adenylcyclase is inhibited, reducing intracellular cAMP (Cyclic Adenosine Monophosphate) levels
   • Which closes Membrane Calcium channels
5. Potassium channels are also opened, releasing cations that make the nerve more negative, and this further from its point of being able to depolarise

These processes, the sum of, result in inhibition of transmitter release between the nerve cells.

Breaking these receptors down, we've got MOP, DOP, KOP, and NOP.

• DOP does pain relief and causes respiratory depression.
• KOP does pain relief, CNS drowsiness, and miosis (those small pupils.)
• MOP, handy again, analgesia causes Miosis, but also is associated with the euphoria, that floaty good feeling can cause respiratory depression, is involved in the sympatholysis, the bradycardia, and unfortunately is also an inhibitor of gut motility, so makes it more constipating.
• NOP receptor, which was initially found and wasn't really terribly well classified, has been identified to bind to a chemical called considered nociception or orphanin.

Nocieptin/Orphanin

• These things don't bind to your mu, delta or kappa receptors and are associated with this suggestion of increased pain.
• It acts in the spinal cord and supraspinally, producing hyperalgesia at low doses, but analgesia at really high doses.

Application clinically.

100 micrograms behaves a bit like 10mg of morphine, Commonly used for very painful but brief procedures, and would be the drug I would reach for to treat severe acute pain in ED Resus, as the onset time of morphine is absolutely pants. It undergoes primary hepatic clearance so a good choice in renal failure and is probably less nauseating given its MOP specificity.

I reach for a big bottle of fentanyl for emergency inter-hospital transfers, as you can 'fill them up' with Fentanyl if you give plenty and obviate the need for an Alfentanil infusion (another pump to tangle, plug in and alarm at you) Give a decent dose at RSI (200mcg) and then titrate the other 300mcg in whilst getting them set up, onto trolley, established on metaraminol. (consider taking some with you- depending on paperwork limitations)

Transcript Fentanyl episode

Introduction and Podcast Overview
00:00-00:34

Please listen carefully. Hello, and welcome to Gas, Gas, Gas, your one-stop podcast for the FRCA primary exam. This podcast will fill your brain with information. Listen to it, think about it, and check out the show notes on the website. There you will find the core diagrams you need to be able to draw and describe for the exam.

This podcast can squeeze into your day. Listen while you're driving to work, cooking dinner, maybe when you're on call, or in the gym. Eventually, the revision is going to end. But for now, expect facts, concepts, model answers, and the odd tangent. Remember to rate and follow the show to hear much, much, much more.

Clinical Context and Uses
00:35-02:39

Hello everyone, this is James at Gas, Gas, Gas. Today we're going to talk about fentanyl, having already had a chat about rocuronium and propofol. It seems reasonable that the third component of your generic anaesthetic that might work for everyone with some tweaks would involve a chat on fentanyl.

Very commonly used opiate, chiefly used as a co-induction agent for anaesthesia, and then you chase it up with some morphine middling to halfway through your case. It's good for early or rapid perioperative pain control if there's a briefly exceedingly stimulating bit, i.e. jabbing that abscess that you're all rooting and excited to do. It's great for post-operative pain control actually.

Its onset time is far superior to morphine and its side effect profile seems to be nicer and kinder compared to morphine. People seem to be a bit more spaced, dizzy, nauseous with morphine compared to fentanyl. And this is in part because it has high specificity to the mu opioid receptor, which is the one that really does pain instead of making you feel awful.

For me, I commonly reach for fentanyl as a co-induction agent. If you're not fussed if they're breathing or not, then give them the whole ampoule - hundred mics. If you're feeling, "Ah, you know what, I want them to breathe quite quickly because it's a quick turnaround case and I don't want too much faff," then actually a mic per kilo or even a bit less than a mic per kilo and wait for the patient to feel it before you induce them will probably preserve them and their breathing more so.

For example, one of the consultants I know just gives about 40 to 50 mics to most people, waits for them to go, "Oh ah, feel a bit - that's nice," and then gives them the propofol. They tend to breathe quite quickly, which is convenient because then you can start writing your notes instead of having to bag them or put them on pressure support or try and ventilate them and then have to fiddle with the ventilator again because they're starting to breathe.

Practical Clinical Applications
02:40-04:29

Other common uses for me: post-operative pain control, getting control of significant pain in recovery quickly, because you can give someone morphine and then you're twiddling your thumbs because it takes thirty minutes to reach peak effect, which is just bonkers if someone's in acute pain.

Often you give morphine and the patient changes, i.e. they get a bit spaced or feel a bit green. And that's the effect that they sometimes have - the titration of morphine to by people titrating it a milligram a time very carefully. I don't like morphine, I think you maybe get that impression.

Fentanyl - bang it in, starts working within a couple of minutes, peak onset five minutes. Yeah, they might stop breathing, but they probably won't if they're in loads and loads and loads of pain, and you're an anaesthetist and you can deal with that by poking them and giving them some oxygen.

Other times I use fentanyl is in the head injured person who needs transfer - use it as an induction agent alongside ketamine, etcetera, but then actually load them up with plenty of fentanyl for that transfer-y busy, busy period, because it hangs around for a while. It means you're not messing around trying to have an alfentanil infusion and a propofol infusion and then transfer a patient in an ambulance somewhere. You can just fill them up with fentanyl. And you know, if you're not waking them up any time soon, then why worry about it?

Fentanyl can also go in other places like in people's noses and into their epidural space and into the intrathecal space, but we'll talk about that in a moment.

I suppose overall what I'm trying to say is fentanyl good, morphine less good, but people tend to reach for morphine because it's highly familiar. You are going to be a specialist, therefore crack on and use the stuff that you know is better for your patient.

Model Answer: Pharmacological Properties
04:29-06:05

Now comes a time in the episode where I vomit verbatim a model answer at you, in order to transfer some of that information about this drug to your brain. It might be a bit tenuous, it might be a bit boring, it might be a bit dry, but ultimately if you can barf this at an examiner, you'll pass the station.

"Doctor, we've heard your preferred opioid of choice is fentanyl. Could you please describe and classify and elaborate on the pharmacokinetics of fentanyl?"

Ah, yeah, I do like fentanyl actually. So fentanyl is an opioid, it's a synthetic opiate. It's a phenylpiperidine derivative of pethidine actually. It is presented as a clear, colourless liquid. Classically its concentration is fifty mics per mil and you can get it in either a hundred microgram ampoules or five hundred microgram ampoules.

Routes of administration include intravenous, oral (although the bioavailability is quite poor), transdermal, intranasal, intrathecal, and epidural, classically. The dose range is actually exceedingly broad and is particular to the operative intervention, so one to one hundred mics per kilo. If you're thinking routine general anaesthesia to thoracotomies, for example, generally speaking, you need seven to ten micrograms per kilo to fully obtund the hypertensive response to laryngoscopy.

Mechanism of Action and Pharmacodynamics
06:05-07:38

So its mechanism of action is it has a particularly high affinity for the mu opioid receptor found in the central nervous system. Its actions include pain relief, sedation, and it's also synergistic with hypnotic agents, i.e. propofol.

Its onset time, one to two minutes to start having an effect with the patient and reaches peak effect within around five minutes. Offset about twenty to thirty minutes. So it's a very convenient opiate for short operating times and for patients in acute pain.

It does have a side effect profile. Cardiovascular effects include bradycardia of vagal origin. This is due to sympatholysis. It doesn't affect your systemic vascular resistance or pulmonary vascular resistance particularly. It has a respiratory depressant effect, as do all opiates, and in very high doses there has been some occurrence of the wooden chest phenomenon or chest wall rigidity.

GI effects: it drops your gastrointestinal motility and reduces acid secretion, also causing sphincter of Oddi closure. This may play an importance in HPB surgery. Classic CNS effects would be mild sedation, the miosis that you'd expect with opiates, i.e. small pupils, and pain relief.

From a metabolic perspective, high doses can ease the stress response associated with surgical intervention. This might play a useful role in very large operative procedures, i.e. your thoracotomies or your extensive laparotomies.

Pharmacokinetics: Absorption and Distribution
07:38-08:29

As I mentioned earlier, it's got poor oral bioavailability, about thirty-three percent. It becomes highly ionised in the stomach, causing slow small bowel absorption. Transdermally, its absorption characteristics improve over time actually.

Distribution wise, it has a pKa of 8.4, so nine percent of the drug is unionised at physiological pH. And that's quite a low volume of distribution: 4.4 litres or 0.88 litres per kilo. Fentanyl is highly protein-bound, 81 to 94%. It is exceptionally lipid soluble, which probably provides most of its onset characteristics, classified as six hundred times more lipid soluble than morphine, which is remarkable really, isn't it?

Metabolism and Elimination
08:29-09:15

Metabolically, its effects are prolonged in patients with liver disease or renal disease. CYP3A4 is involved in its metabolism. It undergoes N-demethylation to norfentanyl, which, along with fentanyl being hydroxylated, both excreted into the urine, and its clearance rate from the plasma is thirteen mils per kilo per minute.

The half-life of fentanyl is one hundred and forty to eight hundred and fifty minutes, depending on the infusion time. Remember it has a high context-sensitive half-life. The more you give for longer, the more you fill the patient, and therefore the longer it takes to all eke out.

So that's the crux of the core content that they might want you to know and understand. And obviously, these points are relevant in your SBAs as well when they're going to be asking you: "What is the volume of distribution of this compared to this, or what's more likely than that compared with that?" Fun times for you.

Clinical Pearls and Advanced Concepts
09:28-10:45

Anyway, moving on to a few more notes and pearls about fentanyl. Other notes with regards to fentanyl: when administered intrathecally or epidurally, it has a very low risk of causing respiratory depression due to it being so exceedingly lipophilic. Why would it go on an adventure out of the nice fatty epidural space or fatty CNS space? Remember, CNS is nice and fatty. Why would it bother going on distal adventures when it can soak in where it's put quite quickly? That's how I imagine it. So it causes less respiratory depression than morphine.

From a metabolism breakdown clearance perspective, there is a suggestion that there's some enterosystemic recycling of the drug - that is you metabolise it, secrete it via bile into your GI tract, you reabsorb it as it has undergone changes in your GI tract, and then it has an effect again, although minimal.

Other things to think about from a kinetics perspective: a single dose redistributes quite quickly, that is, it wants to go and equilibrate throughout all of your fat stores in your body depending on which compartment has the greatest blood flow over time. So the effects of fentanyl drop off as it's redistributed, much like the behaviour of propofol.

Wooden Chest Phenomenon and Related Effects
10:45-11:21

With regards to wooden chest phenomenon, your inhibitory interneurons in your spinal cord at high doses become affected by opioid receptor binding on them, and this leads to a paradoxical increase in chest wall tone - wooden chest - and it's then really hard to ventilate the patient until you paralyse them. Sometimes this is seen in mega-high doses of remifentanil as well.

Naturally, the offset time is faster with remifentanil than fentanyl, but not fast enough that you can't ventilate someone for ten minutes - you might be finding yourself sweating quite a bit and reaching for the paralysing agents.

G-Protein Coupled Receptors and Opioid Receptor Types
11:21-12:45

So now we're going to ponder and talk about this G-protein coupled receptor, of which MOP, DOP, KOP, and NOP are all associated. When something, i.e. a ligand, binds to the receptor site on the G-protein coupled receptor - knowingly there are endogenous versions of things that bind to that, i.e. endorphins and enkephalins, these things called dynorphins, don't ask. Opiates bind to them, but also remember naloxone also binds to these receptors.

A number of things occur within the cell. So you bind your ligand to your G-protein coupled receptor. This undergoes conformational change across the cell membrane. Remember these GPCRs are transmembrane and they have seven transmembrane crossing points described as being serpentine. I'm sure you remember all that from medical school.

A number of things occur: voltage-sensitive calcium channels close, the cell becomes hyperpolarised by potassium efflux from the cytoplasm into the extracellular space, and adenyl cyclase inhibition occurs, leading to reduced cyclic AMP available within the cytoplasm. These processes, the sum of, result in inhibition of transmitter release between the nerve cells.

Opioid Receptor Subtypes and Effects
12:45-14:19

So breaking these receptors down, remember we've got MOP, DOP, KOP and NOP. Your DOP does pain relief and causes respiratory depression. Your KOP causes pain relief, sedation, and the miosis that you see - those small pupils. And then your MOP - handy again - analgesia, causes miosis, but also is associated with the euphoria, that floaty good feeling, can cause respiratory depression, is involved in the sympatholysis, the bradycardia, and unfortunately was also an inhibitor of gut motility, so it makes it more constipating.

The NOP receptor, which was initially found and wasn't really terribly well classified, it's been identified to bind to a chemical called nociceptin or orphanin. These things don't bind to your mu, delta or kappa and are associated with this suggestion of increased pain. It acts in the spinal cord and supraspinally and produces hyperalgesia at low doses, but analgesia at really high doses.

Interestingly, buprenorphine has a partial effect on your NOP receptor. It might be that that's its role in reducing opiate tolerance or morphine tolerance we maybe should say in those who are afflicted with opiate addiction.

Clinical Comparisons and Dosing Considerations
14:19-16:17

So that's talking quite a lot about fentanyl, and we've covered the receptors and how they work. Other things to think about or other things to consider when using fentanyl: a hundred mics of fentanyl behaves a bit like ten milligrams of morphine in terms of pain relief.

Fentanyl is perhaps a better choice in patients with renal failure compared with morphine, because of the primary hepatic clearance really of fentanyl. That's because it undergoes that N-demethylation we mentioned and ongoing hydroxylation of those components, and there are no active metabolites of fentanyl, whereas obviously there are the morphine-3 and morphine-6 glucuronides that are active metabolites of morphine. So fentanyl probably better in a renal failure patient.

If you're really picking something that's only hepatically cleared, then that's buprenorphine, but it's not one that tends to be really used.

That dose range of morphine was a point that really confused me when I started. I was reading all these books, like zero to a hundred mics per kilo, and being quite flabbergasted that everyone was just using a hundred micrograms or seventy micrograms on their patients, and wondering what on earth I'd read.

It took me a while to realise that actually in things like cardiothoracics, long cases that are exceptionally stimulating in patients who might be a bit crumbly and crusty with a knackered heart, humongous amounts of fentanyl as a larger component of your anaesthetic maintenance and induction lead to more stable patients. And you might be horrified to find that they give like a milligram of fentanyl, which is tons. They might just be like, "Here, have this five hundred mic ampoule, and then have another five hundred mic ampoule. Go nuts, they're not going to wake up till Tuesday."

pKa and Lipid Solubility Relationship
16:17-17:35

The thing that was briefly mentioned during all that blurb was pKa. This is something that is good to learn for each of the chief opiates because it gives you some context about their onset times. Fentanyl is a bit of an interesting outlier in this regard. Its pKa is 8.4. Remember, pKa is the pH at which fifty percent of the drug is ionised and fifty percent is unionised.

The unionised bit is the bit that can jump across fatty membranes with ease. So fentanyl, pKa 8.4. When you shift that down to a physiological pH of 7.4, nine percent of it is unionised, which is really actually a very small amount of drug. This is tremendously countered by the lipid solubility. That's what really achieves the excellent onset time of fentanyl - it just piles through that fattiness because of the chemical nature of the compound.

Future Episodes and Conclusion
17:35-18:06

We're going to go into a bit of a deeper dive of pKa in the next run of podcasts, which are going to focus on some of the pharmacokinetic concepts that have come up during these conversations on rocuronium and fentanyl and propofol. We're going to think a bit about volume of distribution, we're going to think a bit about pKa and go from there.

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.