Octreotide

This chapter addresses the surprising expectations of  Section O2(iv) from the 2017 CICM Primary Syllabus, which inexplicably focuses the exam candidate's attention on being able to "describe the pharmacology of octreotide". Since the curriculum was designed, the examiners have only asked one specific question about this drug, for 20% of the total marks in Question 6 from the first paper of 2015. It remains to be seen whether this item will appear in future iterations of the syllabus.

A casual search for this drug yields multiple peer-reviewed articles, many unhelpfully titled "Octreotide". Each has slightly different features which make them useful for different aspects. Indications and complications are explored best by Lamberts et al (1996), pharmacokinetics by Chanson et al (1993) and pharmacodynamics by Battershill & Clissold (1989). The best overall has to be this paper by Chan et al (2013), which presents the drug as a hormonal Swiss army knife, a multipurpose biological instrument with a variety of possible applications. 

Chemical class and chemical relatives

Octreotide is a synthetic peptide analog of the hormone somatostatin, and therefore belongs to the same family as vasopressin and terlipressin. It is a cyclic octapeptide (hence "oct", and presumably also "tide"), consisting of eight amino acids (whereas vasopressin contains nine, and somatostatin itself contains fourteen). This obscure dynasty of organic chemicals contains few members which could be recognised by the normal CICM trainee. All these 'reotides (lanreotide, pasireotide, depreotide, edotreotide, vapreotide, pentetreotide, and on and on) are to some extent or another able to affect somatostatin receptors. This is probably is as familial as this thing is going to get, as the rest of the cyclic peptides are a rather vast and diverse group, and most of them do not have anything to do with endocrinology. One would not feel comfortable grouping octreotide alongside something like gramicidin or cyclosporin, even though technically they are all cyclic peptides with ring-like structures made up of several amino acids.

Administration and bioavailability of octreotide

Octreotide itself has a pKa of 11.4 and its acetate salt is reasonably water soluble (without acetylation the hormone itself would have rather poor water solubility).  It tends to be diluted in saline for administration in ICU, where it tends to be given exclusively as an IV infusion, but a pegylated form is available as an intramuscular depot for people who need their somatostatin receptors activated in a more permanent fashion. As most polypeptides it has very poor oral bioavailability, as it is susceptible to degradation by pepsin and gastric acid. However, the bioavailability is not zero, and simply by giving insanely large doses (say, 20mg) Tuvia et al were able to achieve 80% suppression of growth hormone activity, comparable with a therapeutic parenteral dose of 100 mcg. From this, crude maths suggest an oral bioavailability of 0.5%.

Distribution and protein binding of octreotide

According to Chanson et al (1993), octreotide distributes into 18-30L in normal healthy volunteers, which gives it an apparent volume of distribution somewhere around 0.25-0.4 L/kg. From this, one might come to the conclusion that it mainly likes to hang out in the plasma and extracellular fluid, and this indeed appears to be correct. It is only 65% protein-bound, mainly to lipoproteins, and its preference for the extracellular and circulating volume is probably due to its size (molecular weight is about 1.0kDa). 

Metabolism and elimination of octreotide

Your own homegrown somatostatin is a peptide molecule with an extremely limited half life (2-3 minutes), a property it owes to degradation by plasma peptidases. It was clearly only ever meant to be a paracrine signalling mediator, connecting gastrointestinal neighbours like the stomach and duodenum. Octreotide is of course a completely different molecule, not susceptible to intravascular degradation, and is cleared by a combination of hepatic metabolism and renal elimination (something like 30-50% of the drug seems to escape unchanged in the urine). As the result it has a more respectable half life, in the order of 90 minutes. Still, this means that for a sustained effect this substance must be given as an infusion.

Molecular target and structure-function relationship

Octreotide binds to somatostatin receptors, via a pharmacophore consisting of four amino acids, Phe-Trp-Lys-Thr (Harris, 1994). This appears to be somewhat different to the pharmacophore of somatostatin itself, and therefore this synthetic analogue has a somewhat different receptor selectivity (as do all the other synthetic analogues). There are five such receptor subtypes, and octreotide mainly reaches out to SSTR2, localised mainly to the gut and pancreas, and SSTR5, which is mainly found in the pituitary gland.

Molecular mechanism of action

Somatostatin receptors are Gi-protein coupled receptors. Activation of such a receptor inhibits intracellular cAMP production, and therefore decreases the activity of various cAMP-dependent intracellular enzymes.  It can also directly activate potassium channels, hyperpolarising the membranes of excitable tissues and preventing them from doing whatever they would normally do when excited (which would usually be a calcium-influx-mediated thing). Practically speaking, it appears that most of the clinically relevant effects of somatostatin and its analogues are exerted by the interruption and inhibition of exocytosis (Theodoropoulou et al, 2013), which is how endocrine and exocrine cells typically punt large-molecule mediators out of their storage vesicles. As one might imagine this mechanism is ubiquitous, as are the cells which express somatostatin receptors, making somatostatin a powerful anti-everything hormone. It is occasionally described as "pan-inhibitory" or "pan-antisecretory". If it secretes, somatostatin will inhibit it.

Pharmacodynamic effects of octreotide

Octreotide mimics the regulatory (i.e. mainly inhibitory) activities of somatostatin, which are widespread. Sparing the reader a deep dive into somatostatin physiology, a reference is left here to mark the opening of a massive rabbit hole (Guillermet-Guibert et al, 2005). In the briefest possible summary, the secretion of the following endocrine and exocrine mediators is depressed in a clinically significant way:

• Growth hormone (SSTR2,  SSTR5  and  SSTR1)
• Calcitonin (SSTR1)
• ACTH (SSTR2 and SSTR5)
• Insulin (SSTR2 and SSTR5)
• Glucagon (SSTR2 and SSTR5)
• Interferon-γ (SSTR2)
• Gastric acid (SSTR2)

The bolded receptors are those which are most receptive to octreotide, which should give the reader some impression of the endocrinological effects which they could expect from an octreotide infusion. Also, somatostatin receptors are scattered liberally throughout the gut (Lewin, 1992; Yamada et al, 1992), where they involve nonsecretory tissues:

• Enteric neurons
• Enteric smooth muscle
• Splanchnic vascular smooth muscle
• Splanchnic mucosal secretory cells

Beyond this unfairly gasto-centric selection of sites, somatostatin receptors are widespread throughout the human body. Their expression in lots of different normal and tumour tissue makes their synthetic ligands into excellent radionuclide markers.  Without boring the reader with long discussions of the total breadth and width of what is known about this spread, an excellent table from  Olias et al (2004) will be used here to show what happened to knockout mice when their somatostatin receptors were taken away:

Interested though one might have just become about the exciting cognitive effects of somatostatin and its analogues, one needs to be reminded that CICM put this drug into the gastrointestinal section, rather than the neuro or the endocrine, which should reveal to the trainee what the examiners will be interested in. Thus:

Clinical applications of octreotide for Intensive Care

In short, in the ICU, one may encounter the use of octreotide for:

• Splanchnic vasoconstriction (for GI bleeding or hepatorenal syndrome)
• Intestinal antisecretory activity (mainly to control diarrhoea)
• Decreased flow of chyle (eg. to reduce the accumulation of chylothorax)
• Inhibition of insulin release (for sulfonylurea toxicity)
• Inhibition of various hormones (GH, TSH, serotonin, etc) mainly in the context of neuroendocrine tumours (for example in a state of carcinoid crisis)

This quick summary is all you need for a workmanlike understanding, and after writing the detailed section which follows, the author can comfortably agree that nobody needs to read it. 

Splanchnic vasoconstriction

For GI haemorrhage: Octreotide is able to decrease the blood flow to the gut, which has all sorts of positive implications for the person bleeding from a gastrointestinal source. This is achieved by the inhibition of nitric oxide synthesis. An infusion of octreotide can basically halve the blood flow through the superior mesenteric artery, for example. It also dampens the normal postprandial splanchnic blood flow regulation. This effect has specific benefits in the treatment of GI haemorrhage, as blood presented to the mindlessly uncaring gastrointestinal tract will have the same effect on the splanchnic circulation as food, i.e. vasodilation and increased blood flow. Both arterial and venous bleeding benefits from octreotide, as the systems are connected and a reduction in the splanchnic arterial blood flow logically translates into reduced portal venous blood flow.

For hepatorenal syndrome, the same mechanism is effective. The whole problem in hepatorenal syndrome is excess vasodilation of the splanchnic circulation, into which so much blood flow ends up diverted that the rest of the circulation (including the renal circulation) becomes terminally vasoconstricted by overwhelming sympathetic and neurohormonal responses. Reversing this process by inhibiting splanchnic vasodilation is something octreotide is particularly good at.

Inhibition of insulin 

There are circumstances where it might be useful to be able to suppress the release of insulin intentionally, i.e. where it is for some reason being released in some sort of dangerous and unregulated manner. Historically, this has been the case in the scenario of sulfonylurea toxicity. These ancient and largely disused antidiabetic drugs were forever prone to causing hyperinsulinemic crises, as their main mechanism of action is to depolarise pancreatic β-cells and cause insulin release.  Octreotide counteracts this effect by binding to SSTR5 receptors on pancreatic β-cells, inhibiting the release of cAMP and therefore preventing the release of insulin. The effect can be substantial-  Di Mauro et al (2001), using C-peptide levels as a surrogate for insulin, determined that a continuous octreotide infusion at a rate of around 100 μg/day dropped the rate of insulin secretion by something like two-thirds. In the modern era of safe effective drugs for Type 2 diabetes this application is largely forgotten, as nobody is really dependent on dangerous doses of sulfonylureas. Still, people occasionally present with insulinoma or congenital hyperinsulinism which calls for chronic suppression therapy.

Inhibition of growth hormone secretion

The reader is reminded that the name "somatostatin" comes from its first observed  biological activity, first noted by Brazeau and Guillemin in 1973 after the pair processed litres of sheep hypothalamus extract and found a peptide which inhibited the release of growth hormone at nanomolar concentrations.  The tedious name chosen by the original investigators ("hypothalamic growth hormone inhibiting factor") appears to have been abandoned in basically the same year, as all the subsequent publications on this topic in 1973 were calling it "somatostatin" instead.  Anyway: for conditions where growth hormone secretion is for some reason excessive (eg. in acromegaly), octreotide is the standard solution. It suppresses the release of both GH and GHRH, and is effective in cases of both pituitary and ectopic sources. Instead of exhausting the impatient exam candidate with another irrelevant biochemistry appendix, this section will conclude with a link to an excellent free article by Murray et al (2004), which covers all the central and peripheral GH-related actions of somatostatin.

Inhibition of thyroid stimulating hormone release

Like it inhibits everything release, octreotide inhibits TSH release. But to thyroid hormone release. Which makes it an excellent response to a TSH-secreting pituitary "thyrotropinoma", a tumour sufficiently rare that many professional readers will not be familiar with the term. For a variety of reasons it is beneficial to treat these things with hormone suppression either instead of, or along with, surgery. The use of octreotide is not uniformly successful here, as some TSHomas may decide to be unresponsive to somatostatin (tumours being anarchists with little respect for normal cellular signalling).

Suppression of carcinoid syndrome crises

Octreotide significantly improves the flushing and diarrhoea associated with the release of serotonin and other preformed inflammatory molecules from carcinoid neuroendocrine malignancies. Again, the mechanism of this is thought to be something to do with octreotide interfering with the exocytosis of vesicle-stored mediators, which is how all those molecules happen to be stored. Unfortunately, this is somewhat difficult to prove, as we really have no idea of which mediators cause the occasionally life-threatening manifestations of carcinoid syndrome  (Kallicrein? Neurotensin? Substance P? Histamine, bradykinin, serotonin?). 

Either way, when these life-threatening manifestations do arise, these people do often end up in the ICU, surrounded by excited endocrinologists. The mediators, whatever they are, can produce various horrible vasomotor effects, be they vasodilation and shock or hypertensive crises.  In those scenarios, octreotide seems to be an excellent means of aborting the release of these noxious substances.  Without digressing any further on a topic that really belongs in the small-font footnotes of the Fellowship Exam section, the reader is instead left with a reference that describes the use of octreotide in this setting (Warner et al, 1994). 

Inhibition of random neuropeptides (eg. VIP)

A discussion of the actions of octreotide inevitably involves the discussion of secretory tumours, and that discussion inevitably ends up in a thicket of rare and exotic weirdomas. To be sure, if you can think of some obscure paracrine mediator, there's probably an adenoma somewhere that's prepared to secrete it, and there's a decent chance that octreotide will have an inhibitory effect on this activity. Into this  wastebasket category go the VIPomas, glucagonomas, gastrinomas, and so forth. There's probably no massive benefit to listing them here.

Inhibition of intestinal secretory activity

There are scenarios where intestinal secretory activity is either dysregulated or becomes inconvenient for some sort of surgical reason. Possible situations where this happens can include:

• Pancreatic fistula
• Small bowel fistula
• Biliary fistula
• Secretory diarrhoea 
• High output stoma (where the fluid and electrolyte loss is unsustainably demanding)

For these, to slow secretory activity is beneficial because:

• It slows the flow through a fistula (allowing it to potentially heal and close)
• It slows the transit of intestinal contents (allowing it to be absorbed, which could mean the difference between being on TPN and not being on TPN)

Paran et al (1995) were probably the first to report on the effect of octreotide in this setting. In case anybody is wondering, a high output fistula is one which produces more than 500ml per day; and this is exactly the sort of fistula that octreotide was the most helpful for, reducing the flow rate by about 60%. A reduction in output was seen within the first 24 hours of therapy. The main mechanism here seems to again be the inhibition of hormone activity - this time, secretin cholecystokinin and VIP, all of which stimulate gastrointestinal motility and secretion. The decreased motility, in turn, allows for longer transit, and therefore enhances absorption of water and electrolytes, decreasing the total volume. Harris (1992) elaborates extensively on these mechanisms over 54 pages, in case the reader feels the need for a deep dive into early somatostatin/octreotide lore.

Decreased flow of chyle

It is not that one complains undesirable excess of chyle flow, but that a normal amountof chyle flow becomes a major liability when it ends up spilling into some sort of body cavity (like a chylothorax), or directly out of the body (eg. where one has accidentally injured the thoracic duct in the course of a neck dissection). . Interestingly, there does not seem to be a good explanation by exactly how it decreases chyle flow, and authors seems to make various vague allusions to the decrease in splanchnic blood flow or intestinal secretion. It certainly seems to rapidly and effectively decrease the rate of chyle flow (by about two thirds, in a dog study by Markham et al, 2000). This was enough to help the medical management in a series by Jain et al (2015), who reported on their experience of using octreotide for the management of chylous neck fistulas. Even high-flow fistulas dried up after about five days of therapy.

Analgesic and palliative effects

For certain (mainly malignancy-associated) conditions, often refractory to other pain relief strategies, octreotide can have analgesic properties. The mechanisms for these are mainly related to its prevention of growth (eg. tumour cell proliferation) or its effect on gastrointestinal secretion (reducing the flow of something towards a painful malignant obstruction, for example). Specific use cases can include:

• Hypertrophic pulmonary osteoarthropathy
• Malignant bowel obstruction (it relieves the colic)
• Chronic pancreatic pain from pancreatic duct stenosis
• Bone pain from metastatic neuroendocrine tumours

Adverse effects of octreotide

As one might imagine in the case of a substance with so many different effects, there can be no clinical situation where all of them are equally desirable, and so logically the rest will be either a nuisance or frankly harmful. It is remarkable how well-tolerated it is in clinical trial populations, who mainly complain about bloating and steatorrhoea (due to the reduced biliary flow). For critical care, Borna et al (2017) approaches the drug from the view point of the anaesthetist, from whose perspective none of the effects are especially desirable. 

Other serious potential effects include things like:

• Impaired wound healing (via its effect on growth hormone) 
• Hyperglycaemia (reduced insulin secretion)
• Hypothyroidism
• Hypoadrenalism
• Anorexia, nausea and weight loss
• Bradycardia, conduction abnormalities, and arrhythmias
• Biliary sludge and cholelithiasis (mainly by promoting biliary stasis)