Ep 25 – DiaMorphine

Introduction and Clinical Anecdote

[00:00 – 00:45]

Hello everyone and welcome to Gas, Gas, Gas. We’re cracking on with yet another episode in our joyful opiate-flavoured pharmacology jaunt of a chapter. Today we are doing heroin, or we should say doing diamorphine.

First anecdote of this podcast is when I accidentally told a patient’s father that I was going to give them heroin up their nose to make it easier to put their finger straight, because it was wonky. Error. The kid, as you might expect, was like, “yeah, I’m on that.” And then I realised the error of my ways and the backtracking was challenging. So first tip of the day: don’t tell kids you’re going to squirt heroin up their nose. Just say it’s a nice painkiller.

Drug Classification and Formulation

[00:45 – 01:30]

Key Points:

• Synthetic diacetylated morphine derivative (di = two acetylations)
• Available as powder for reconstitution
• Comes in 1mg, 5mg, or 10mg ampoules

Righto. So diamorphine is an opioid, everybody. And it’s a synthetic diacetylated morphine derivative. Di, two acetylations. Acetylated, there are acetyl groups.

How does it come? So it comes as a powder for reconstitution in a variety of quantities. It can be either 1mg, 5mg or 10mg in an ampoule depending on what’s available. It can be administered intravenous, intramuscularly, intrathecally, epidurally and intranasally. I’m sure there’s a bunch of other routes as well.

Mechanism of Action

[01:30 – 02:15]

Cellular Mechanisms:

• Acts on G-protein coupled opiate receptors
• GI protein subunit triggers intracellular cascade
• Results in diminished neurotransmission via hyperpolarisation

How does it work? Well, as we all well know nowadays, it works on G-protein coupled opiate receptors. The subunit on the inside of that cell is a GI protein. And it triggers a number of mechanisms within that cell that leads to diminished transmission by way of hyperpolarising that cell membrane. It does this by opening potassium channels, closing calcium channels, and inhibiting adenylyl cyclase, leading to less cyclic AMP available.

Clinical Indications

[02:15 – 03:30]

Primary Uses:

• Potent analgesia in palliative care
• Neuraxial administration (epidural/intrathecal) by anaesthetists
• Intramuscular administration for labour pain (midwifery)
• Acute left ventricular failure (reduces preload)

So, diamorphine, what do we use diamorphine for? Unsurprisingly, we use it for pain. It is a potent analgesic. However, when do we use this potent analgesic?

It’s certainly something that is sometimes reached for in the palliative care environment. Anaesthetists classically reach for this when delivering opiates to someone’s CNS, i.e. epidural or intrathecal. Midwives in some hospitals are giving it IM for pain relief in labour. And, you know, as you might expect, it behaves like morphine. So if someone has crashing pulmonary oedema, left ventricular failure, we need to drop their preload and make their sensation of breathing better, you could use diamorphine. Although, more classically, people do reach for morphine on the wards.

Dosing Guidelines

[03:30 – 04:15]

Standard Doses:

• Epidural: 2.5-5mg
• Intrathecal: Up to 500mcg (300mcg often optimal for benefit vs side effects)

Ah yes, so what is the dose of diamorphine? Well, like with any drug, your dosing’s limited by the side effect profile of that drug, and diamorphine is no different. So, you could give all the diamorphine in the world, but you would find yourself in a very painful situation and having to have a long conversation with someone more senior, saying, “why on earth did you do that?”

But generally speaking, 2.5-5mg as an epidural dose and up to 500mcg as an intrathecal dose. Although some papers would suggest that 300mcg is the point where you’re going to see the most benefit against the most side effect.

Side Effects Profile

[04:15 – 06:30]

System-by-System Effects:

Cardiovascular:

• Reduced systemic vascular resistance
• Orthostatic hypotension (fine lying down, BP drops on standing)
• Bradycardia (in megadoses)
• Histamine release

Respiratory:

• Diminished depth and rate of breathing
• Impaired cough reflex

Central Nervous System:

• Potent analgesia
• Drowsiness
• Euphoria
• Hallucinations (sometimes)
• Delirium (if unfortunate)
• Pruritus (itching)

Gastrointestinal:

• Reduced motility
• Nausea and vomiting
• Constipation
• Sphincter of Oddi spasm

Genitourinary:

• Urinary retention (bladder relaxation)

So we’ve talked about side effects here. What side effects could there possibly be with such a drug? Now we all know that you can kick out a verbatim opiate side effect answer and move on with the exam, but all these opiates remember do have slightly different side effect profiles because different molecules can bind to other receptors lurking around the body, not just opiate receptors. They always can sneak along in, you know, pethidine they were planning for that to be like atropine.

Pharmacokinetics

[06:30 – 09:00]

Absorption:

• Good oral absorption but extensive first-pass metabolism
• Limited bioavailability via oral route

Distribution:

• 40% protein bound
• Volume of distribution: 350 litres
• pKa: 7.6
• 34% unionised at plasma pH (cf. fentanyl 9%, morphine 23%)

Metabolism:

• Diamorphine is a prodrug
• Highly lipophilic in diacetylated state
• Converted by esterases (pseudocholinesterase, red blood cell esterases)
• Diacetylmorphine → 6-monoacetylmorphine (active) → morphine
• Morphine glucuronidated to morphine-3-glucuronide and morphine-6-glucuronide

Elimination:

• 50-60% excreted in urine as morphine derivatives
• Active metabolites renally cleared
• Morphine-6-glucuronide accumulates in renal failure (sedating effects)

Reversal:

• Naloxone (as expected)

So how good are we at absorbing diamorphine? Well, great oral absorption – it gets straight into that venous circulation of your GI tract. However, your liver is a busy little sausage and there is extensive first-pass metabolism, so it doesn’t really make it past the liver if you just go and eat a load of opium. Well, diamorphine – we’re being specific here aren’t we?

Upcoming Episodes Preview

[09:00 – 10:00]

So that was a whistle-stop tour of diamorphine. Now, as you might expect, I got quite carried away reading about how opiates traverse our CNS space, i.e. epidural and intrathecal opiate administration. This was clearly going to be far too big a topic to smash through, and I wanted to be specific to diamorphine.

So I’m going to do an extra episode. It’s going to come out probably on Monday, where we talk about how they came about sticking opiates in people’s CSF spaces, how they work, how they move around the CSF space, and the things to consider when weighing up drug choice for intrathecal or epidural opiates. And we can have the excitement of thinking all about octanol-water partition coefficients. Oh, how exciting, guys! But actually, more importantly, having a deeper understanding of how these opiates shift around in the intrathecal space can really ground your understanding of why we choose what dose and what drug in what region. So it’s going to be an exciting one. Don’t miss it.

Then after that, we’re going to do remifentanil and look at the Minto TCI model. And then I think, I hope, we have done the opiates chapter and we can move on to maybe local anaesthesia because that’s an important anaesthetic-y type of thing.

Closing Remarks

[10:00 – 10:30]

Anyway, cheers for listening guys. Have a nice weekend. 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.

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.