This chapter addresses the surprising expectations of  Section O2(v) from the 2017 CICM Primary Syllabus, which for some reason singles out the ability to "describe the pharmacology of terlipressin" as an essential quality of a successful exam candidate. To be sure, terlipressin is interesting, and in some circles surely regarded as the most significant advance of man since roads and sanitation, but one still wonders exactly how much one would need to learn about it, considering no questions about it have ever been asked in the CICM exams. The intensivist would come across it only infrequently, in the course of managing severe gastrointestinal bleeding from uncontrolled varices, or as an adjunct to the management of hepatorenal syndrome. 

Name Terlipressin
Class Vasopressor
Chemistry Cyclic peptide
Routes of administration IV, IM, s/c
Absorption Degraded by gastric acids and enzymes; oral bioavailability 1%
Solubility pKa = 10; good water solubility
Distribution VOD = 0.6-0.9L/kg; minimally protein-bound
Target receptor Terlipressin and its active metabolite have about six times more affinity for the V1 vasopressin receptors (vasoconstrictor effect), as compared to V2 (antiduretic) receptors.
Metabolism Mostly metabolised into lysine vasopressin (porcine analogue of human arginine vasopressin) by endotheial peptidases
Elimination Terlipressin is almost completely metabolised; lysine vasopressin is eliminated parly by hepatic endothelial peptidases and partly by renal clearance.
Time course of action Half-life of terlipressin is about 50 minutes, but because the daughter molecule is an active drug, the duration of the effect is ~ 6 hours
Mechanism of action Vasopressor effects are exerted by V1 receptors, which are Gq-protein coupled receptors. Similarly to alpha-1 receptors, they increase intracellular calcium by means of increasing cAMP concentrations.
V2 receptors are Gs-coupled receptors and produce the insertion of aquaporins into the apical membrane of principle cells of the collecting tubule.
Unlike catecholamine receptors, vasopressin receptors do not lose their affinity for vasopressin with changing pH.
Clinical effects Vasoconstriction, redistribution of splanchnic blood flow, modest antidurtetic effect. Clinically important effects on the splanchnic circulation include decreased mesneteric blood flow, and therefore decreased portal venous pressure, which is the desired effect for control of variceal bleeding and hepatorenal syndrome.
May worsen coronary ischaemia and diastolic dysfunction.
Single best reference for further information Pesaturo et al (2006)

Pesaturo et al (2006) is probably the single best peer-reviewed reference for the revising exam candidate, and probably the only reference one needs to recommend, as sound advice to such a candidate would include a warning against wasting their time reading too many papers about terlipressin. 

Chemical class and chemical relatives

Terlipressin is a synthetic peptide analog of the hormone vasopressin, and therefore belongs to the same family as octreotide. It is structurally different from the parent molecule (8-arginine-vasopressin) because it has had a triplet of glycine molecules appended to its cysteine residue (hence the "ter") and is otherwise based on the lysine-containing porcine variant of the hormone (8-lysine-vasopressin), hence the "li". Or at least, that's what one could reasonably conclude - but in fact there is no official published explanation for the prefix "terli", and all the statement above are purely speculative. For all we know, "terli" in incorporated into the generic name because it means "sweaty" in Turkish. Lypressin (containing lysine) and argipresin (containing arginine) suggest glypressin as the natural progression for this glycine-heavy drug, and indeed it also goes by that name, but only as a registered trademark for some reason.

Administration and bioavailability of terlipressin

Like basically all peptide drugs, terlipressin should be highly susceptible to degradation by gastric and pancreatic proteases. There does not seem to be a peer-reviewed publication to back this, but the descriptions of some animal studies in this patent read like conference abstracts, suggesting someone somewhere actually carried out this research and submitted it to the scrutiny of at least their lab supervisor. The investigators were able to achieve therapeutic plasma levels with oral doses of around 20mg, which suggests a bioavailability of 1%. Considering the expense of its manufacture and the scope for its use, most people prefer to administer it intravenously or subcutaneously.

Distribution and protein binding of terlipressin

Terlipressin, or at least the commercially available acetate salt of terlipressin, is highly water soluble and has a pKa of 10. The volume of distribution is small, 0.6-0.9 L/kg, as befits a relatively large molecule finding it difficult to diffuse across compartment boundaries. There does not seem to be any clinically significant protein binding.

Metabolism and elimination of terlipressin

Here, terlipressin is at its most interesting. The triglycyl molecule ends up being de-triglycylated, if that's a word. The three glycines are cleaved off the parent molecule by endothelial peptidases, and what remains is lysine vasopressin, of the same sort that the pituitary gland of a domestic pig might produce (Forsling et al, 1980). This process takes a while, which means that terlipressin basically behaves as a slow release pro-drug,  gradually becoming converted into "proper" vasopressin with a half-life of about fifty minutes. The result is a duration of effect of around 4-6 hours (Nilsson et al, 1990). Lysine vasopressin is metabolised in much the same way as arginine vasopressin, mainly by the endothelial peptidases of the liver (with a fair proportion of it escaping unchanged in the urine). 

Molecular target and structure-function relationship

The V1 and V2 vasopressin receptors are molecular targets of terlipressin and lysine vasopressin. The different molecular tails are the most importan

  • Lysine vasopressin, the main daughter molecule of terlipressin, exerts its effects by binding to V1 and V2 receptors, and has full agonist activity but with lower antidiuretic and pressor potency than arginine vasopressin (Van Dyke et al, 1956)
  • Terlipressin itself has some V1  and V2 effects as well, but the magnitude and clinical significance of these is debated. Forsling et al (1980) found some vasopressor effects developing already within three minutes of its administration, long before lysine vasopressin levels started to increase, suggesting it was having an intrinsic pressor effect. However, its affinity for these receptors is about 100 times lower than that of lysine or arginine vasopressin, and it appears to be a partial agonist. 

Both terlipressin and lysine vasopressin have a higher affinity for the V1 receptor than for the V2 receptor, with a ratio of 6:1 (Jamil et al, 2018), which means their antidiuretic effects should be expected to be modest. That is in fact what you see clinically: the antidiuretic effect is clearly there (Krag et al, 2008), but it is not impressive, specially if by treating hypotension you have in fact improved the perfusion of the kidneys. Many authors using terlipressin in the field actually report an improved urine output, probably reflecting the resolution of shock. 

Molecular mechanism of action

The chapter on vasopressin explains this in more detail, and with diagrams. In short, V1 and V2 receptors are Gq and Gs protein coupled receptors, respectively, and both of them tend to increase the concentration of intracellular cAMP which then acts a second messenger. The downstream effect in vascular smooth muscle is the increased availability of intracellular ionised calcium, and therefore vasoconstriction.

Pharmacodynamic effects of terlipressin

At normal doses the main effects of terlipressin are splanchnic vasoconstriction and some increase in the tonicity of the urine, associated with its water-retaining effects. By redistributing blood volume out of the splanchnic vascular territories, terlipressin exerts its main therapeutic effects: namely, the decreased perfusion of arterial or venous bleeding sites in the gastrointestinal tract, and the reversal of the harmful splanchnic distribution of body water which promotes the development of hepatorenal syndrome. That the latter happens was demonstrated by several studies such as Kiszka‐Kanowitz et al (2004), who subjected cirrhosis patients to whole-body scintigraphy. After 30 minutes, terlipressin caused a decrease of splanchnic regional blood volume by about 1.8%.

The selectivity of terlipressin for the splanchnic circulation is a much-touted feature, but is not always demonstrated by the data. For example, Morelli et al (2004) had demonstrated an increase in gastric mucosal blood flow following the bolus administration of terlipressin, likely because they were measuring it in patients who were severely shocked and required high doses of noradrenaline (0.6 mcg/kg/hr). As terlipressin corrected the relative vasopressin insufficiency in these patients, the blood pressure improved and the noradrenaline dose was turned down, allowing and improvement in splanchnic perfusion.

Adverse effects of terlipressin

The abovementioned redistribution of blood flow towards the splancnhic circulation could not have happened unless terlipressin had substantial systemic vasoconstrictor effects. V1 receptors are everywhere and terlipressin definitely causes widespread systemic vasoconstriction by acting on them. Depending on what precious structure is being supplied by the vasoconstricting vessel, those effects may be undesirable. Probably the most unpleasant of these undesirable vasoconstrictor side effects is coronary vasoconstriction, which has been observed enough times to produce several case reports, and a concern that the intraoperative use of terlipressin may unmask hidden ischaemic heart disease. The unexpected increase in afterload can also exacerbate diastolic failure, worsen mitral regurgitation, and produce subendocardial ischaemia even with normal coronaries. 


Pesaturo, Adam B., Heath R. Jennings, and Stacy A. Voils. "Terlipressin: vasopressin analog and novel drug for septic shock." Annals of Pharmacotherapy 40.12 (2006): 2170-2177.

Kulkarni, Anand V., et al. "Terlipressin has stood the test of time: Clinical overview in 2020 and future perspectives." Liver International 40.12 (2020): 2888-2905.

Nilsson, G., et al. "Pharmacokinetics of terlipressin after single iv doses to healthy volunteers." Drugs under experimental and clinical research 16.6 (1990): 307-314.

Van Dyke, H. B., Stanford L. Engel, and Karlis Adamsons Jr. "Comparison of pharmacological effects of lysine and arginine vasopressins." Proceedings of the Society for Experimental Biology and Medicine 91.3 (1956): 484-486.

FORSLING, MARY L., et al. "Conversion of triglycylvasopressin to lysine-vasopressin in man." Journal of Endocrinology 85.2 (1980): 237-244.

Ryckwaert, Frédérique, et al. "Terlipressin, a provasopressin drug exhibits direct vasoconstrictor properties: consequences on heart perfusion and performance." Critical care medicine 37.3 (2009): 876-881.


Jamil, Khurram, Stephen Chris Pappas, and Krishna R. Devarakonda. "In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2." Journal of Experimental Pharmacology 10 (2018): 1.

Krag, Aleksander, et al. "Effects of terlipressin on the aquaretic system: evidence of antidiuretic effects." American Journal of Physiology-Renal Physiology 295.5 (2008): F1295-F1300.

Morelli, Andrea, et al. "Effects of terlipressin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock." Intensive care medicine 30.4 (2004): 597-604.

Kiszka‐Kanowitz, M., et al. "Effect of terlipressin on blood volume distribution in patients with cirrhosis." Scandinavian journal of gastroenterology 39.5 (2004): 486-492.

Medel, Jessica, et al. "Terlipressin for treating intraoperative hypotension: can it unmask myocardial ischemia?." Anesthesia & Analgesia 93.1 (2001): 53-55.

Lee, Min‐Yi, et al. "Terlipressin‐related acute myocardial infarction: a case report and literature review." The Kaohsiung Journal of Medical Sciences 20.12 (2004): 604-608.