Vasopressin

Gas Gas Gas: Vasopressin and its Pals (FRCA Primary)

An EduCast untangling vasopressin, desmopressin and terlipressin: receptors, physiology, clinical use and kinetics

---

Introduction: Welcome to Gas Gas Gas

00:00 – 00:45

Please listen carefully.

Hello, Team Anaesthesia. Welcome to Gas Gas Gas. This is the best anaesthetic science podcast for the FRCA Primary exam. Our goal is to fill your brain with all this highly useful information.

Now, you might be in the gym right now, commuting, or ironing your scrubs, and there’s no judgement here. Gas Gas Gas will prime your brain for the monsoon of knowledge you need to imbibe. But regardless, the revision is eventually going to end. But for now, expect facts, concepts, model answers, and the odd tangent.

Now remember to check out the website, that’s gasgasgas.uk. There are show notes there with all the detail, plus links to foundational reference papers and anything else useful I find for you guys.

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

---

Episode Preamble: Untangling the Pressins, and a Shout-Out to Dr Ben Knox

00:46 – 02:10

Hello everyone, and welcome to another episode of Gas Gas Gas. Please excuse the late-night DJ voice; the nine-month-old is sleeping.

Quelle surprise, this episode is focusing on trying to untangle what vasopressin is, where it is used, what desmopressin is compared to it, and how terlipressin relates to it as well. We’ll try and tease these things apart so that we can make sense of it when it’s two o’clock in the morning, you’re on call for intensive care, you don’t feel like you’re an intensive care doctor, but you need to start these drugs.

Just before we get into the thick of it, I’d like to give a shout-out to Dr Ben Knox, a trainee in Northern Ireland. Sounds like he’s subjected himself to the entire gaggle of episodes. He comfortably passed the Primary SBA in September, and he’s looking forward to the viva in February. Sounds like he’s been listening whilst he’s been running. He dropped me an email to say thank you very much, and even though he nearly turned off the episode when I started waffling on about EMLA cream one day, he’s glad that he didn’t. A eutectic mixture of local anaesthetics: prilocaine and lidocaine, folks. Oh, exciting, but it comes up in the exams.

So keep listening, keep practising. Well done. And make sure to introduce yourself as Dr Knox, knocks you out, to the right patient [?]. I’m very jealous of the surname. Bravo.

Let’s get on with it. I’m not here to deliver a vapid monologue on vasopressin, but there are certainly a couple of interesting pearls to at least tickle your neurons ever so slightly.

---

Why Vasopressin Matters to the Anaesthetist

02:11 – 03:17

So first up, vasopressin is absolutely relevant to the anaesthetist. You’re probably not going to be reaching for it in your first month of anaesthesia when someone’s a smidge hypotensive, but you will find yourself using it on intensive care, wondering what on earth it is, and trying to understand when you start it, when you turn it off, how much you give, and what it really does.

Later on in your career you may come across it being used in theatre. Either it’s a desperate situation where you’re starting vaso in theatre: someone who’s floridly septic, the wheels have fallen off, the norad’s on 0.8, and you’ve all gone and started the vaso [?]. That patient is unlikely to be long for this world, but you never know. If you’ve started, you may as well finish. Or someone’s coming off bypass and they’re terribly vasoplegic because it’s been a really long case. And finally, you may be taking a patient to theatre who is on norad and vaso because something’s gone wrong in their tummy and they need an operation, in which case most would recommend not fiddling with it too much.

So you’ve probably come across either vasopressin or terlipressin, or maybe even desmopressin, already.

Key points

• On intensive care, vasopressin is the second agent for catecholamine-refractory septic shock.
• In theatre: refractory septic shock, vasoplegia after a long bypass run, or a patient arriving already on noradrenaline and vasopressin.

---

Three Molecules: Vasopressin, Desmopressin and Terlipressin

03:18 – 04:29

Now, why on earth are there three different types of drug? Surely they all act on the same receptor. We’re going to get into the thick of that, but the crux is this. If we’re talking about ITU vasopressin, this is more or less straight-up antidiuretic hormone, or arginine vasopressin. It is interchangeably called all three.

If we’re talking about desmopressin, this is a similar but different molecule, which is 10 times as potent when it comes to causing the antidiuretic effects of vaso, but literally can’t do a thing for blood pressure: it’s 1,500 times less potent. It’s also referred to as DDAVP. That’s its brand name, but it’s also because it’s 1-desamino-8-D-arginine vasopressin, or 1-deamino-8-D-arginine vasopressin, hence the DDAVP.

And our terlipressin friend is a long-acting version. Terli-, because it’s triglycyl-lysine vasopressin. It’s a prodrug activated by endothelial peptidases, and it lasts about six hours.

Assume, unless I say otherwise, that we’re talking about the bog-standard arginine vasopressin, a.k.a. ADH. Right.

Key points

• Vasopressin, arginine vasopressin (AVP) and antidiuretic hormone (ADH) are the same molecule.
• Desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin): 10 times the antidiuretic potency, 1,500 times less pressor potency.
• Terlipressin (triglycyl-lysine vasopressin): a long-acting prodrug activated by endothelial peptidases, lasting about 6 hours.

---

Drug Class, Routes, Origin and History

04:30 – 05:52

So what class of drug is that? Well, it’s a peptide hormone, actually. You can imagine that peptide hormones are precarious things to ingest orally, because we have these things called peptidases that are quite peckish when it comes to peptides and break them down. So you would expect to mostly give these drugs subcut, IV, IM, etc.

Important to note that extravasation of vasopressin causes necrotic, ischaemic badness, so we really want to make sure that goes in a nice, well-placed central line. DDAVP can be IM or oral.

So it’s a naturally occurring nonapeptide pro-hormone, synthesised in the paraventricular and supraoptic nuclei of your hypothalamus.

Cheeky bit of history? Its vasopressor activity was first observed in 1895. It was called pituitary extract, because I think they were just getting some pituitaries, probably not of humans, but who knows, probably pigs, grinding them up, sloshing them around with some fluid of some sort, I presume, and sticking it in people to see what would happen. As you can imagine, that doesn’t tend to happen quite so much in the modern era of medical science. Eighteen more years went by from 1895 before the antidiuretic effect was also noticed, and it was synthesised in a lab in the 1950s.

Key points

• Vasopressin is a peptide hormone, so it is given IV, IM or subcut. Desmopressin can also be given orally.
• Extravasation causes ischaemic necrosis, so give it through a central line.
• Synthesised in the paraventricular and supraoptic nuclei of the hypothalamus.
• Pressor activity of pituitary extract was noted in 1895, the antidiuretic effect 18 years later, and the hormone was synthesised in the 1950s.

---

Isomerism, Presentation and Molecular Weight

05:53 – 06:44

Is it an isomer? Well, yes, but there’s no real clinical relevance. It demonstrates cis–trans isomerism.

Presentation. The presentation depends on whether you’re good old-fashioned vasopressin, terlipressin or desmopressin. Desmopressin comes either as an IM, subcut or IV solution, or as an oral tablet, whereas terlipressin is either a powder or a clear liquid, and vasopressin is a clear, colourless solution.

Its molecular weight, if you’re curious, is 1,083 or so grams per mole. So biggish, but they’re not going to ask you that in the exam, so don’t worry about it. Although I’m sure if you were ever asked in the exam, “Oh, and what’s the molecular weight of that drug?”, you could say, “Well, around about 1,000 grams per mole,” and they’d move you on, because nobody really knows any of this stuff. So don’t worry about it too much. You’ll be fine. Just study.

Key points

• Shows cis–trans isomerism, which has no clinical relevance.
• Vasopressin is a clear, colourless solution. Terlipressin is a powder or clear liquid. Desmopressin comes as an IM, subcut or IV solution or an oral tablet.
• Molecular weight is about 1,083 g/mol.

---

SBA Question: Vasopressin in Septic Shock

06:45 – 07:45

Right, everyone, time for a question on vasopressin, courtesy of the Teach Me Anaesthetics team.

A 39-year-old female is on intensive care, being treated for pyelonephritis with septic shock. She’s on 0.5 micrograms per kilo per minute of noradrenaline to maintain her blood pressure. However, her noradrenaline requirement is increasing. The decision is made to commence vasopressin as a second agent. What is the most important action of vasopressin in this context?

A. Stimulation of V1 receptors to increase water resorption and plasma volume.

B. Stimulation of V2 receptors to increase water resorption and plasma volume.

C. Stimulation of V1 receptors to induce vasoconstriction.

D. Stimulation of V2 receptors to induce vasoconstriction.

E. None of the above.

And you’d be right: C, stimulation of V1 receptors to cause vasoconstriction, is the correct answer.

Key points

• In septic shock, the action that matters is V1 receptor-mediated vasoconstriction.
• V2 receptors mediate water reabsorption, not vasoconstriction.

---

Physiology: Synthesis, Transport and the Drivers of Release

07:46 – 10:01

Okay, so before we go into the pharmacodynamics, the clinical effects and the kinetics of vasopressin, it’s certainly worth reminding ourselves a little bit about standard vasopressin physiology: where it comes from, that sort of thing.

So I mentioned it is synthesised in the paraventricular and supraoptic nuclei of the hypothalamus. You may have stumbled across them being called magnocellular neurones in your textbooks when you did your neuroanatomy at medical school. Vasopressin is transported into the posterior pituitary from the hypothalamus down the supraopticohypophyseal tract. What the floof is hypophyseal, you ask? It’s a fancy old-fashioned name for the pituitary.

What drives release of vaso? Now, you must know this one. Yes, indeed: plasma osmolality is the biggie. You have these osmoreceptors. You have central ones, but interestingly you also have peripheral ones, and these osmoreceptors expand and contract and cause signalling that says, “Hey, we’re too salty,” or “We are too watery, and we’re terribly upset by this. He’s clearly had four Domino’s pizzas over here. We need to do something.” And hypovolaemic stimuli as well, but it’s really plasma osmolality, folks.

I said they were central and peripheral. There I was, thinking that there were only central osmoreceptors. Turns out I’m clearly a fool, because you will find them in the hepatic portal veins, and they relay their signal via the vagus nerves. Cool.

But no, the central ones, clearly more important, are found lurking near the third ventricle, in a patch of the third ventricle which doesn’t have a blood–brain barrier. Cool. And it has a long and headache-inducing name, which might creep out of some orifice of a neurone somewhere in your mind: the OVLT, or the organum vasculosum of the lamina terminalis. Rolls off the tongue. That’s alongside the subfornical organ: subfornical, fornix, another part of the brain. Basically, say third ventricle, central osmoreceptors, boom. And interestingly, remember, no blood–brain barrier, because it needs to be able to rapidly assess what’s going on.

Key points

• Made in the magnocellular neurones of the supraoptic and paraventricular nuclei, then carried down the supraopticohypophyseal tract to the posterior pituitary.
• Plasma osmolality is the main driver of release. Hypovolaemia also triggers it.
• Central osmoreceptors sit in the OVLT and subfornical organ by the third ventricle, outside the blood–brain barrier.
• Peripheral osmoreceptors in the hepatic portal veins signal via the vagus.

---

Tangent: Circumventricular Organs and the Embryological Brain

10:02 – 11:16

There are a bunch of bits of the brain with no blood–brain barrier, for the curious among us. One that you probably should know for the exam is the area postrema, and this is one of the sensing elements for the vomiting centre. You know, that bit that communicates with the chemoreceptor trigger zone, blah, blah, blah, all that. The area postrema: floor of the fourth ventricle, detects toxins in blood, no blood–brain barrier. Pineal gland: located near the roof of the diencephalon.

Remember, the diencephalon is a group of brain structures that includes the thalamus, hypothalamus, etc. If we go back to our historic neuroanatomy, and again, folks, this ain’t in the exam, it’s just to refresh your brains, there’s the telencephalon, the diencephalon, the mesencephalon, the metencephalon and the myelencephalon. And I remember these by the mnemonic “tel-di-mesi-met-myelen”, which is courtesy of a bloke I went to medical school with, and it’s always just stuck in my brain: “tel-di-mesi-met-myelen”. And you can reel off those clever defining structure groups of the brain that are derived from the embryological beginnings of the brain. Told you you’re going to learn something. Oh, exciting.

Okay, right, back on track, because we’re trying to be sensible here and learn stuff for the exam, as opposed to just things you can talk to medical students about.

Key points

• Circumventricular organs have no blood–brain barrier: the OVLT, subfornical organ, area postrema (floor of the fourth ventricle, detects blood-borne toxins) and pineal gland.
• Brain vesicles: telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon.

---

Normal Osmolality, and Osmolality versus Osmolarity

11:17 – 12:34

So, normal vasopressin physiology. We know that when it senses that you’re too salty, it causes release of vasopressin, or ADH, increases your free water retention, and tries to return you back to a normal-ish osmolality.

What is normal osmolality in a human? Again, they could ask you this. Many different numbers are quoted, but I would argue between 280 and 295 milliosmoles per litre.

And again, in the exam, they may well ask you the difference between an osmolality and an osmolarity. Osmolality is the number of osmotically active substance per kilo. It’s very inconvenient, but the osmolal with an extra L does not refer to litres. Thanks, whoever did that. Cheers. And osmolarity, with an R, is the solute per litre.

I can’t tell you how to remember that. I just remember that if it’s got two Ls in, it must be inconvenient, and therefore it’s the one that’s kilos, not litres. But you need to think of a way yourself to remember that delightful factoid.

Welcome to the FRCA Primary exam, where your hopes and dreams are either blooming and blossoming in a field of tulips, or falling down a deep and dark cavern. Either way, there is light somewhere.

Key points

• A rise in osmolality triggers ADH release and free water retention, which brings osmolality back towards normal.
• Normal plasma osmolality is about 280–295 mOsm/kg.
• Osmolality is osmoles per kilogram of solvent. Osmolarity is osmoles per litre of solution.

---

Why Physiological Vasopressin Doesn’t Raise Blood Pressure

12:35 – 13:54

The effect we’re interested in with vasopressin, you don’t really see in a normal physiological human. It doesn’t really cause an increase in blood pressure of any true relevance at the concentrations you will find knocking about in the plasma of a human. Because it would be a bit daft, wouldn’t it, to release vasopressin that stops you losing water, in fact makes you retain water, but then squeezes your blood vessels and puts your blood pressure up, even though you’ve got more water circulating in your plasma volume. That’s useful if you’ve just been hit by a car or mauled by a sabre-toothed tiger, but not useful if you’re just lightly twiddling to keep your plasma osmolality normal. So you don’t actually see the vasoactive, blood pressure-increasing effects until you vastly exceed the normal physiological levels of vaso.

You will also come to learn that there’s a diminishing effect. So once you’ve put someone on vaso, you think, “Oh gosh, they’re going to get hyponatraemic, they’re going to hold on to all this water.” We know that ITU patients are doing that anyway, although sometimes they get hypernatraemic, because the game of ITU is: are they too wet or too dry? But it’s diminishing returns. After a certain amount of vaso, it doesn’t do that to any greater degree, because it’s literally at the physiological limit of what it can exert upon the kidney.

Okey-dokey, what a lovely little segue.

Key points

• At physiological concentrations vasopressin has no relevant pressor effect. Vasoconstriction appears only well above physiological levels.
• The antidiuretic effect plateaus, so higher infusion rates don’t keep increasing water retention.

---

A Breather: The SBA Answer Explained

13:55 – 14:41

Anyway, before we talk about the true clinical effects of vaso and its pharmacodynamics, we need to do a bit more of the sciencey stuff and think about the receptors. This would be a good moment to just have a quick breather if you’ve had your face melted off by what we’ve just gone through, because you’re going to have to put your face, I don’t know, in a bucket of ice and drop your heart rate for the next bit.

Vasopressin, when used as a vasopressor, binds to V1 receptors. These are Gq-coupled G protein-coupled receptors, leading to an increase in intracellular calcium within the smooth muscle of the vascular tree, leading to vasoconstriction. Thanks to Teach Me Anaesthetics.

Right, let’s get back into it.

---

Vasopressin Receptors and the V1 Receptor

14:42 – 16:29

You sound ready. So what sort of receptors does vasopressin act on? Overarching: these are G protein-coupled receptors, as well as oxytocin receptors. There are several different types of vasopressin receptor, and if you’re reading the literature, there’s sometimes a bit of a mess of nomenclature. The accepted way is calling them a vasopressin 1 receptor, a vasopressin 2 receptor and a vasopressin 3 receptor. They all have slightly different effects.

So, V1Rs, or VP1s; some people call them VP1s. If you read that, or someone refers to it like that, don’t panic. V1Rs, vasopressin 1 receptors, are found in high densities in vascular smooth muscle, but also on platelets, in the kidneys, all over the place. They cause profound vasoconstriction in skin, skeletal muscle, fat and mesentery. But they don’t cause much vasoconstriction, usefully, in the cerebral and coronary circulations. And vasopressin 1 receptors are Gq-linked G protein-coupled receptors.

Again, they ain’t going to be asking you this truly deeply in the exam, but if you’re sat on ITU titrating these as an ITU reg, or a consultant intensivist, or a consultant anaesthetist, I think it’s reasonable that we should have a scientific understanding of the things we’re doing. Yes, you’re studying for the FRCA Primary exam, but I want you to just be a good doctor with good scientific knowledge, not just a guideline-following individual. That’s what makes us different. We actually know how things work.

Okay, Gq-linked. That does the phospholipase C, increased calcium, with the diacylglycerol and the IP3, PIP2 stuff going on. It causes vasoconstriction because more calcium makes smooth muscle more contracty. We’re going to go into that in more detail later.

Key points

• There are three vasopressin receptors (V1, V2, V3), all GPCRs. Vasopressin also acts on oxytocin receptors.
• V1 receptors sit on vascular smooth muscle, platelets and in the kidney. They are Gq-coupled: phospholipase C, then IP3 and DAG, then a rise in intracellular Ca²⁺ and vasoconstriction.
• They constrict skin, skeletal muscle, fat and mesentery strongly, but the cerebral and coronary circulations only a little.

---

V2 Receptors: Water, von Willebrand Factor and Desmopressin

16:30 – 18:28

Vasopressin 2 receptors, or V2Rs. These are chiefly found in the kidney, in the distal renal tubules and collecting ducts, on the endothelial cells there. Again, G protein-coupled, Gs-linked, and these activate adenyl cyclase, increasing cyclic AMP. That does some clever stuff that inserts aquaporin 2 channels into the apical cell membranes, causing water resorption. So that’s the water resorption bit.

But interestingly, you will also find these V2 receptors in the vascular endothelium, and they do something quite spooky and clever. Again, that might make you think that vasopressin has utility when you’ve been mauled by, I don’t know, Charlie the sabre-toothed tiger, because it causes your vascular endothelium to release von Willebrand factor that’s just sort of hanging around there waiting to do some business.

And therefore you can give a drug that agonises the vasopressin 2 receptor in order to make patients with von Willebrand disease a bit better before a surgeon gets their hands on them. It also has clinical utility in patients with a factor VIII deficiency, i.e. haemophilia A, although they don’t really know why it helps. There are a few suggestions, but it turns out that it just does. Arguably, it’s good for mild haemophilia A, as opposed to rip-roaring, bleeding-to-death-ness, in which case you probably want to give them something with that clotting factor in it instead.

If we circle back to those three types of vasopressin-y molecules that we mentioned, the good old-fashioned antidiuretic hormone, vasopressin, argipressin, the terlipressin or the desmopressin: I bet you can think which one the haematologists like us to give folk before they go for surgery if they have von Willebrand deficiency or a mild factor VIII deficiency. And that is desmopressin, DDAVP. You can give it IM an hour or so before the operation, and it makes everything quite a bit nicer.

Key points

• V2 receptors are Gs-coupled. Adenylyl cyclase raises cAMP, which inserts aquaporin-2 into the apical membrane of collecting duct (principal) cells, so water is reabsorbed.
• Endothelial V2 receptors release von Willebrand factor.
• Desmopressin (DDAVP) is given before surgery in von Willebrand disease and mild haemophilia A. Severe haemophilia needs factor replacement.

---

A Haemophilia Mnemonic

18:29 – 19:07

Now, yet another clinical pearl to distract you from the monotony, and a potentially useful reminder if you somehow get on to haemophilia in the exam. Probably more a Final thing than a Primary thing. We all should know that there’s haemophilia A and haemophilia B. How on earth do you remember which factor it is? Well, haemophilia A, eight: factor VIII. Banging. Haemophilia B, benign: factor IX. Although we can totally agree that it’s not benign. Although it is benign in the fact that once upon a time it was called Christmas disease. Lovely time, Christmas. Benign. Except it’s not benign. It’s bad for your health.

Key points

• Haemophilia A is factor VIII deficiency. Haemophilia B (Christmas disease) is factor IX deficiency.

---

V3 Receptors and Other Actions

19:08 – 20:13

Okay, and then I did dangle that delightfully exciting carrot, not for Rudolph, but for you. When it comes to the vasopressin 3 receptor, these are Gq-linked like the vasopressin 1 receptor. However, they are found in the pituitary and they cause ACTH release. Remember, that’s the thing that goes on to make your steroid-producing tissues produce glucocorticoids.

And then finally, other things vasopressin seems to do on, like, a biochemistry level: it modulates nitric oxide synthesis, and it modulates the ATP-sensitive potassium (K-ATP) channels, which are implicated in that vasoplegic mess of sepsis. And it potentiates the effects of adrenergic agents, which is why it’s quite synergistic when someone is hoovering up the norad like no tomorrow, and actually a bit of vaso reduces their norad requirements quite markedly.

Ooh, I’m teaching you lots about vasopressin today. And if I’m honest, folks, I learned quite a bit when I was putting this episode together as well. Is there really ever going to be an opportunity to mercilessly quiz a medical student on this? No, unless one wants to come on the show. So, well, anyway.

Key points

• V3 receptors in the pituitary are Gq-coupled and stimulate ACTH release.
• Vasopressin also modulates nitric oxide synthesis and K-ATP channels, and potentiates adrenergic agents, which is why it lowers the noradrenaline requirement.

---

Clinical Effects: Oxytocin Receptor Crosstalk

20:14 – 21:35

Vasopressin: well, the clinical effects of vaso. So we spoke about how obviously it causes free water retention and increases blood pressure, but it also acts on oxytocin receptors. Now, why on earth does that happen? Well, from an evolutionary standpoint, if you go back around 700 million years, there is a prototypical vasopressin–oxytocin hormone. They diverged, and they actually only differ by, like, two amino acids. But there’s a bit of crosstalk, as vasopressin likes to tickle oxytocin receptors, and oxytocin doesn’t say no to a vasopressin receptor.

They are both produced in the posterior pituitary, and it is of clinical relevance to the anaesthetist inasmuch as a long oxytocin infusion in an excessive dilution, as you might routinely give to a severe pre-eclampsia patient, A, is going to give them a volume burden, and B, is going to make them stop peeing, when you really want them to start peeing once they’ve delivered. They’re really oedematous, and they would normally start peeing unless they’re on a massive oxytocin infusion, and then they get hyponatraemic. Folks do get hyponatraemic on oxytocin infusions when the obstetricians are desperately trying to keep that uterus clamped down.

Don’t ask me if carbetocin has the same degree of effect. I don’t know. You only give it once, and it does work for longer, but at least you’re not giving it with loads of fluid as well.

Key points

• Vasopressin and oxytocin come from one ancestral hormone and differ by two amino acids, so each acts on the other’s receptors.
• Long, dilute oxytocin infusions (e.g. in severe pre-eclampsia) add a fluid load, cause antidiuresis and can cause hyponatraemia.

---

Onset, Duration and Clinical Uses

21:36 – 22:41

Onset time of vaso when you start it on ITU? Well, you’re not going to be bolusing it, are you? So you’re going to start an infusion. You’re going to expect that to take about 15 minutes before you start seeing something. The bedside nurses will generally start titrating the norad down, so you could probably work out the onset time in your patient by seeing when the norad started coming off.

Offset, or duration of action: the plasma half-life is 10 to 35 minutes.

Its clinical utility: as I mentioned earlier, it’s great in catecholamine-refractory shock, when the norad’s not really working. It could be reached for in cranial diabetes insipidus and bleeding varices, and I think once upon a time they did. If you look in the BNF, you could give 20 units of vaso to treat bleeding varices. Doesn’t happen any more.

And the only niche time it might be reached for in theatre is when you’ve inadvertently anaesthetised someone who’s on a reasonably good-going dose of losartan [?] or candesartan, or, if you’re unfortunate, an ACE inhibitor that they’ve taken. They can end up with profound hypotension that is refractory to standard treatment, but vasopressin seems to do the trick.

Key points

• An infusion takes about 15 minutes to act. Plasma half-life is 10–35 minutes.
• Main use: catecholamine-refractory shock. Historically also cranial diabetes insipidus and bleeding varices (20 units), no longer used for those.
• In theatre: hypotension that doesn’t respond to standard treatment in a patient who has taken an ACE inhibitor or an angiotensin receptor blocker.

---

Dosing: Vasopressin, Terlipressin and Desmopressin

22:42 – 23:52

Dosing. So naturally, you should follow local practice. Don’t go nuts. I found out that where I have worked, where they go up to four units an hour of vasopressin, it turns out that might be a bit too much. And if you’re listening, Dr Clinton: yes, that patient in bed three is on 3.69 units per hour of vasopressin. Thank you very much.

Terlipressin: one to two milligrams every four hours. That’s given IV.

And desmopressin: one to four micrograms per day, often given in split doses. Give one microgram; it seems to work really well. When someone has cranial diabetes insipidus, most likely you’re going to see this in a patient who’s going through the process of brain death on intensive care. They start peeing for England, and desmopressin just clamps that off beautifully.

And on the subject of clamps, a niche use of DDAVP is to stop the diuresis associated with the correction of hyponatraemia, because they have a different osmolar set point in the hypothalamus, apparently. You can do a DDAVP clamp to control their free water loss and then very slowly adjust their sodium back up. Again, niche use. I’m not going to tell you how to do that; you need to follow local guidelines. The Internet Book of Critical Care talks about that, and it does seem to work quite nicely.

Key points

• Vasopressin: follow the local protocol. Some units go up to 4 units/hour, which is probably too much.
• Terlipressin: 1–2 mg IV every 4 hours.
• Desmopressin: 1–4 micrograms/day, often split. Cranial diabetes insipidus is common during brain death on intensive care.
• A DDAVP clamp stops the free water diuresis, so sodium can be corrected slowly in hyponatraemia.

---

Effects and Side Effects

23:53 – 25:12

Anyway, that was the sort of clinical, pharmacodynamic-y side of things for vasopressin. What about the effects and side effects? Now, naturally, in the exam you can say that it increases the systemic vascular resistance, but in excessive doses it can cause profound vasoconstriction and impair distal perfusion, mesenteric perfusion, etc., and this can be injurious.

It doesn’t do anything to your breathing, although it does relax your pulmonary vasculature and reduce your pulmonary vascular resistance, which your myocardium, of the right ventricular variety, is really going to appreciate on intensive care, because your right ventricle does work pretty hard pumping against positive pressure ventilation, etc., etc.

It mildly reduces urine output, and obviously desmopressin does so far more than vasopressin does.

Now, interestingly, you’re probably sat there thinking, “Yeah, but why does terlipressin not make my patients have a blood pressure of 10.3 million when I’ve given it to them? Is it because they’ve got blood loss?” And whilst it probably helps that they’ve got some blood loss, vasopressin in animal models (obviously you can’t really test humans in this regard): well animals don’t respond terribly well to vasopressin. It doesn’t really do much to their blood pressure. But when you are vasoplegic and critically unwell, you become far more sensitive to the blood pressure-improving effects of vasopressin. Blimey.

Key points

• It raises SVR. Too much causes profound vasoconstriction, with distal and mesenteric ischaemia.
• It has no respiratory effect, but it lowers pulmonary vascular resistance, which helps the right ventricle.
• It causes mild antidiuresis (desmopressin causes much more).
• Vasoplegic, critically ill patients are far more sensitive to its pressor effect than healthy subjects.

---

Pharmacokinetics

25:13 – 26:10

Okay, pharmacokinetics. This one’s quite brief. Absorption: well, we’ve mentioned that DDAVP has an oral route, but when we’re talking about vasopressin, there is no oral bioavailability, as the peptidases in your GI tract tidy it up quite well.

Distribution-wise, its volume of distribution is quoted as 0.14 litres per kilo. Apparently its protein binding ranges between 50% for DDAVP and about 30% for vasopressin. Thank you very much, Deranged Physiology. We are forever in your debt for these niche data points.

Metabolism-wise, I’m going to tie this in with elimination. 65% of vasopressin is excreted unchanged in the urine. 35% is broken down by tissue peptidases, which are lurking in a person. Now, you can imagine that peptidases probably shouldn’t be too busy in a human, because they might start breaking down the human. Nevertheless, apparently some seem to exist, and they are chiefly found on vascular endothelium. Obviously, they do exist in the GI tract.

Key points

• No oral bioavailability, because GI peptidases destroy it. Desmopressin can be given orally.
• Volume of distribution is 0.14 L/kg. Protein binding is about 30% for vasopressin and 50% for desmopressin.
• 65% is excreted unchanged in the urine and 35% is broken down by tissue peptidases, mainly on vascular endothelium.

---

Sources, and a Discombobulating Paper

26:11 – 26:49

Oh, well, that was a serious journey into vasopressin. Now, you’d be disappointed to hear that Peck and Hill doesn’t even talk about vasopressin, at least in the edition I have, and the Handbook of Experimental Pharmacology also doesn’t really talk about it. As for the sources, they’re referenced in the show notes. There are a couple of papers.

There’s one paper that I chose to chuck in the bin, and that’s a review paper that sounds like it’s been written by AI. I’ve not experienced that before, but it piles in, starts blathering on, doesn’t set the scene at all. It’s a really discombobulating paper. Hopefully that’s not the case with this podcast episode. I really hope that you are thoroughly combobulated.

---

Physiology Refresher: How Vascular Smooth Muscle Contracts

26:50 – 28:56

Anyway, have a breather. We’re going to just ponder a few more physiological thoughts, because, you know, we do need to learn physiology for the exams and for our general practice. Physiology is coming later with Gas Gas Gas. Obviously, there’s quite a lot of work that goes into all of these episodes, and I chose pharmacology because I knew I would just get far too excited with physiology. But it turns out I’ve just got far too excited with pharmacology as well.

Anyhow, a couple of thinking points and questions. We should probably remember how smooth muscle in the vasculature normally contracts. Definitely Primary FRCA physiology knowledge; hopefully this is revision for you.

But the muscle apparatus inside your smooth muscle myocytes… Remember, your blood vessels are made of three layers. You’ve got your tunica intima, tunica media and tunica externa, slash adventitia. The intima is your endothelial layer and basement membrane. The media is where you’re going to find your smooth muscle. The adventitia is the connective tissue bit.

So now we are down at our smooth muscle myocytes, and we know that they are really dependent on calcium concentration within the cell to trigger contraction. There are a number of things that increase the calcium fraction inside the cell, which we’re going to get into in a minute. But ultimately, more calcium binds to calmodulin, which is a protein knocking around inside the cell that activates a number of phosphokinases. We’ve got myosin light chain kinase, which phosphorylates; phosphorylation means you get contraction. And then you’ve got myosin light chain phosphatase, which, as you can imagine, dephosphorylates and puts the brakes on contraction.

We’re imagining that we’ve got a lovely phosphorylated piece of myosin. It costs ATP to phosphorylate the myosin, but now this lovely phosphorylated myosin is able to increase its myosin ATPase activity, causing the conformational change that allows the heads of the myosin to bind to actin and perform their fun cross-bridge vibes and create tension.

Key points

• The vessel wall has three layers: tunica intima (endothelium), tunica media (smooth muscle) and tunica adventitia (connective tissue).
• Ca²⁺ and calmodulin activate myosin light chain kinase. Phosphorylated myosin gains ATPase activity, and actin–myosin cross-bridge cycling generates tension.
• Myosin light chain phosphatase dephosphorylates myosin, and the muscle relaxes.

---

Calcium In, and Relaxing Smooth Muscle

28:57 – 30:17

Okay, so yeah, but how does all that calcium actually get in there to bind to calmodulin and start all that stuff going? Good question. Well, anything that increases calcium in the cell… And we can all remember that we have calcium channel blockers; they’re going to decrease calcium in the cell. But then we’ve got things like noradrenaline, which is a Gq-linked GPCR agonist that increases calcium availability within a cell, but then angiotensin will also do that, and vasopressin, as we’ve discussed, will also do that.

The counter to that, things that reduce calcium availability in a cell: well, when we’re talking about smooth muscle in the vasculature, which is a target for antihypertensive agents, amlodipine is an excellent example, an L-type dihydropyridine calcium channel blocker.

Finally, what are the physiological methods by which the relaxation of smooth muscle can be modulated? We’ve naturally got a bit focused on things that improve blood pressure, but there are things within the body that calm the blood pressure down as well. Chiefly, that’s going to be your atrial natriuretic peptide, ANP, which tips that balance between myosin light chain kinase, which phosphorylates, and myosin light chain phosphatase, which dephosphorylates, in favour of the latter, increasing the rate of dephosphorylation of myosin and reducing tension. And nitric oxide, activated by cyclic GMP-dependent kinases, also triggers that.

Key points

• Noradrenaline, angiotensin II and vasopressin (all acting on Gq-coupled receptors) raise intracellular Ca²⁺.
• L-type dihydropyridine calcium channel blockers such as amlodipine lower it.
• ANP and nitric oxide relax smooth muscle through cGMP and cGMP-dependent protein kinase, tipping the balance towards myosin light chain phosphatase. Nitric oxide activates soluble guanylate cyclase to make cGMP.

---

Summary: Vasopressin in Practice

30:18 – 32:04

Oh, godly gosh, wow, we’ve talked a lot. I should probably summarise. Vasopressin is a common critical care drug for the catecholamine-refractory, vasoplegic, wheels-falling-off sepsis patient, but it’s also found clinical utility in patients with vasoplegia who’ve been on prolonged cardiopulmonary bypass. It is the vasoactive agent of choice in patients who’ve been diagnosed as brainstem dead if they are awaiting organ retrieval. And it has a bit of a niche [?] if you’ve somehow anaesthetised someone who’s taken all their ACE inhibitors and their angiotensin receptor blockers and you’ve been unlucky.

I’m pretty sure you are allowed to anaesthetise patients who’ve taken an ACE inhibitor nowadays. It used to be that you asked the patient to stop it; it’s generally fine. But every now and again, you might see quite profound hypotension. And you shouldn’t be anaesthetising folks if they’ve taken their angiotensin receptor blocker. That’s still a no-no. Always worth having your ephedrine and your metaraminol to hand if you are embarking upon that anaesthetic in the person who’s taken three antihypertensive agents, because it can involve a degree of mischief.

Remember, it’s a peptide hormone. The dose range goes up to four units an hour where I work, but I think that’s too much. Most places go a bit lower than that; follow your local guidelines. The side effect profile is permissible, but in high doses you cause profound vasoconstriction. They can look really mottled, they can lose perfusion to their fingertips, and you can cause organ ischaemia.

And if you’re getting into the long grass in the exam talking about vasopressin, either the examiner is being very unkind to you and letting you journey off into the long grass and waste time, or you’ve passed the station, or it’s a station on the detailed use of vasopressin and you’re actually sitting the FFICM. Good luck to you if you are.

Key points

• Uses: catecholamine-refractory septic shock, vasoplegia after prolonged bypass, the brainstem-dead organ donor, and refractory hypotension after ACE inhibitors or angiotensin receptor blockers.
• Have ephedrine and metaraminol ready when anaesthetising a patient on several antihypertensives.
• Follow the local dosing protocol. High doses cause mottling, loss of perfusion to the fingertips and organ ischaemia.

---

Sign-Off and a Dobutamine Teaser

32:05 – 32:45

Anyway, thank you very much for listening. I hope you’ve all had positive outcomes with your exams this time around. If not, keep listening, pick yourself up, have a cup of tea. It’ll all be okay next time. And on that joyful note, thank you very much for listening to Gas Gas Gas.

In two weeks’ time, we’re going to be dabbling with dobutamine. If you think you need to give your patient dobutamine, make sure you draw it up, put it in a tray, and then disappear on your transfer, leaving that tray in resus, and be sat in that ambulance thinking, “Oh, bugger. I do have more dobutamine, thank God, but I’ve got to draw it all up again, and I feel like a silly sausage.” Don’t leave your painstakingly drawn-up drugs in resus when you pile into an ambulance. Just don’t. Have a checklist. Right, bye.

---

Outro

32:46 – 33:37

Ahoy, Team Anaesthesia. You’ve survived yet another episode of Gas Gas Gas. Now, if you found it useful or harrowingly awful, please like and subscribe, drop us a star or twelve, and follow with whichever podcast platform you find yourself using. Please leave a comment or ping off an email if you think I need to square something away.

Now, there are a bunch of ways to support the costs of Gas Gas Gas, from buying me a coffee to venturing forth via an affiliate link to the horde of joyful SBA questions from Teach Me Anaesthetics. Those links are on the website and in the show notes.

Speaking of the website, definitely check out gasgasgas.uk for the show notes, diagrams, details and the references. Now, we all know, guys, that this is a bucket of content to consume, and it is like drinking from a fire hose. So I want to finish by saying: take it day by day, don’t overcook yourself, don’t freak out, and keep studying.