This chapter is related to Section U2(vii) from the 2023 CICM Primary Syllabus, which expects the exam candidate to understand the pharmacology of vasopressin and its analogues, and so is a dreary repetition of several vasopressin-related chapters from all over the CICM exam syllabus. To be fair, in the actual syllabus document vasopressin really only appears in the endocrinology section, but realistically it would be amiss to leave it out of the cardiovascular section, or to ignore it where the regulation of body water is discussed, or to gloss over it in the discussion of sepsis management. As the result, vasopressin and vasopressin-like drugs appear in several other pages, listed below for reader convenience:
Even though all this material exists somewhere in another form, it still seemed reasonable to bring it all together in this summary, considering especially it is an Official Syllabus Item. Having said this, First Part Exam endocrinology questions have never asked anything about the pharmacology or physiology of vasopressin, but Question 22 from the second Fellowship Exam paper of 2009 somehow did, and it even included the specific phrase vasopressin and its analogues. From this, it might appear that this syllabus item really belongs in the Part Two exam, considering especially that the CICM First Part already existed in 2009.
Anyway: rather than to just dump all the vasopressin class content from the local CICM First Part Exam Pharmacopoeia, it felt more professional to discuss these peptides as a class, and to go through their pharmacology systematically, pointing out unusual features along the way. This has already been done by Glavaš et al (2022) so comprehensively that the amateur writer may despair, concluding nothing further could possibly be added. Wherever a reader finds an unsupported fact in the text below, it likely comes from Glavaš et al. For a more intense deep dive into vasopressin physiology the reader may also be directed to the two papers by Holmes et al (1992, Part 1 and Part 2).
8-arginine vasopressin is a synthetic analogue of an endogenous nonapeptide hormone where the eighth amino acid molecule is an arginine. It is indistinguishable from the endogenous hormone which is secreted by the posterior pituitary of humans, and is only slightly different from porcine vasopressin, which contains a lysine in same position instead.
It is a cyclical peptide: The two cysteines are joined by a disulfide bridge, and this curls the molecule into a donut.
Since its discovery in 1895, pituitary extract has been just that- extract of pituitary glands, fresh or dried. Specifically, the glands of oxen, it would seem. Interest in its clinical use (and, one must assume, the practical inconvenience of having to extract, dry and process industrial quantities of bovine pituitary glands) has ultimately led to the de novo synthesis of it by du Vigneaud in 1955 (he had already synthesized oxytocin by the same method, and received the Nobel Prize in Chemistry for it).
Combined with 0.5% chlorobutanol as a preservative, it comes in a 1ml ampoule of 20 pressor units per ml.
What the hell is a pressor unit, you ask?
The pressor unit is defined as a quantity of pressor agent which is equivalent in pressor activity to the activity of 0.5 milligram of the USP Standard Powdered Pituitary U.S.P., a USP posterior pituitary reference standard. Yes, there is a standard of pressor activity, analogous to the platinum rod used as the international standard of the metre, or to the unit standard of heparin (keeping the liquid state of refrigerated cat blood, etc.)
Like the metre, it is ancient, and like the rabbit seizure unit measurement of insulin it has a weird history. Dale and Laidlaw first described the standard in 1912, before the actions of the different posterior pituitary hormones were known. The infundibular extracts were tested on the uterus of the virgin guinea pig, which was found to contract with nicely predictable linear responsiveness to successively increased doses of the extract. However, subsequent modifications of the method resorted to using rat uterus, the authors complaining about the expense of obtaining guinea pigs in post-war Britain. As the difference between the two posterior pituitary hormones became apparent in coming years, and as synthetic analogues became available, the USP units became separated into the oxytocic unit (used to compare uterine activity) and the vasopressor unit (used to compare the effect on the blood pressure of the rat).
The USP standard was a homogenised extract of the posterior pituitary, weighing about 20mg, which was distributed to laboratories in the 1950s to standardise the purification of posterior pituitary hormones. The definition is used to this day, even though now there are better ways to measure vasopressin dose. Synthetic vasopressin is very pure and potent; 1 mg of pure vasopressin corresponds to about 600 pressor units.
Numerous variations of the basic molecular structure of vasopressin exist; or rather, vasopressin and its analogues in humans and other animals are all some variations on the same common theme which probably arose in unimaginably ancient times, likely along with such fundamental animal features as bilaterality (though it must be noted that even radially symmetrical animals like the starfish have neuropeptides structurally similar to vasopressin which do various vasopressin-like things). As most people would not have much interest in the reproductive hormones of molluscs, no further attention will be given to these substances here, considering especially that we have plenty of manmade vasopressin analogues to discuss. To tabulate a diagram from Glavaš et al (2022), their appearance in pharmacology can be chronicled as follows:
