Identification

Summary

Terlipressin is a drug used to treat bleeding caused by esophageal varices.

Brand Names
Terlivaz
Generic Name
Terlipressin
DrugBank Accession Number
DB02638
Background

Terlipressin is a synthetic analogue of vasopressin, which is an endogenous neurohormone that acts as a vasoconstrictor.1 It is a prodrug of lypressin, or lysine vasopressin. Compared to endogenous vasopressin, terlipressin has a longer half life and increased selectivity for the V1 receptor.8 As a potent vasopressor, terlipressin has been investigated in various shock states and conditions with diminished vasomotor tone.1,2,3,4,5 It was also studied in hepatorenal syndrome (HRS) and variceal bleeding.6 The drug was first approved by the FDA in September 2022.8

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Hormones
Protein Chemical Formula
C52H74N16O15S2
Protein Average Weight
1227.38 Da (as free base)
Sequences
>Terlipressin Seq
GGGCYFQNCPKG
References:
  1. PubChem: Terlipressin Compound Summary [Link]
Download FASTA Format
Synonyms
  • Terlipresina
  • Terlipressin
  • Terlipressina
  • Terlipressine
  • Terlipressinum

Pharmacology

Indication

Terlipressin is a vasopressin receptor agonist indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function. The US prescribing information states that patients with a serum creatinine > 5 mg/dL are unlikely to experience benefit from terlipressin.8

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Terlipressin mimics the biological effects of endogenous vasopressin, but it displays increased selectivity for the V1 receptor and a longer half-life than vasopressin. These pharmacokinetic and molecular properties of terlipressin give it several advantages, such as the prevention of rebound hypotension when the drug is stopped 1,3 and convenience in patients with limited intravenous access.1

Terlipressin increases arterial pressure (diastolic, systolic, and mean) and decreases heart rate in patients with hepatorenal syndrome type 1 (HRS-1). After the administration of a single 0.85 mg dose of terlipressin in patients with HRS-1, cardiovascular effects were observed within five minutes after dosing and were maintained for at least six hours after dosing. The maximum change in blood pressure and heart rate occurred at 1.2 to two hours post-dose.8

Mechanism of action

Endogenous vasopressin, also referred to as antidiuretic hormone (ADH) or arginine vasopressin (AVP), regulates important physiological processes such as osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning.7 It is a nonapeptide synthesized in the hypothalamus and stored in the posterior pituitary.1 Vasopressin mediates its biological effects by binding to three subtypes of vasopressin receptors.5 V1 receptors are expressed on vascular smooth muscle and many other cells such as hepatocytes: activating these G-protein-coupled receptors leads to vasoconstriction. V2 receptors are predominantly expressed on the basolateral membrane of the distal tubule and collecting ducts of the kidney: these receptors are responsible for the antidiuretic effect of vasopressin, regulating water permeability of kidney tubules and therefore maintaining water homeostasis.1 V3 receptors mediate the effects of vasopressin on the central nervous system.5

Vasopressin is considered a stress hormone as it is released into the bloodstream in response to various volume and pressure stimuli, such as pain, surgery, syncope and shock.1,5,7 Shock conditions such as hypovolemia initially cause an increase in the release of vasopressin to maintain organ perfusion; however, as the shock state progresses, plasma vasopressin concentrations decrease due to several causes such as depleted stores of vasopressin in refractory shock and a central inhibitory effect of initially elevated vasopressin levels on further vasopressin release.5

Terlipressin is a synthetic vasopressin analogue that can cause sustained increases in blood pressure in patients with shock conditions.5 It exhibits twice the selectivity for vasopressin V1 receptors versus V2 receptors. Terlipressin is pharmacologically active but acts as a prodrug for lypressin (also known as lysine vasopressin), a vasoconstrictor and antidiuretic agent. The exact mechanism of action of terlipressin is not fully understood; however, terlipressin works to cause vasoconstriction in shock and other conditions associated with vasodilation. Hepatorenal syndrome (HRS) is caused by splanchnic and systemic arterial vasodilation along with a reduced mean arterial pressure (MAP) and cardiac output, resulting in a marked decrease in effective circulating volume.6 Terlipressin is thought to increase renal blood flow in patients with HRS-1 by reducing portal hypertension and blood circulation in portal vessels and increasing effective arterial volume and mean arterial pressure (MAP).8

TargetActionsOrganism
AVasopressin V1a receptor
agonist
Humans
AVasopressin V1b receptor
agonist
Humans
AVasopressin V2 receptor
agonist
Humans
Absorption

Following a 1 mg IV injection of terlipressin acetate in patients with HRS-1, the median Cmax, AUC24h and Cave of terlipressin at steady-state were 70.5 ng/mL, 123 ng × hr/mL and 14.2 ng/mL, respectively. The median Cmax, AUC24h and Cave of lypressin were 1.2 ng/mL, 11.2 ng × hr/mL and 0.5 ng/mL, respectively. Terlipressin and lypressin exhibit linear pharmacokinetics in healthy subjects. Plasma concentrations of terlipressin demonstrate proportional increases with the dose administered.8

Volume of distribution

The volume of distribution of terlipressin was 6.3 L and 1370 L for lysine-vasopressin.8

Protein binding

Not Available

Metabolism

The N-terminal glycyl residues of terlipressin is cleaved by various tissue peptidases to release its pharmacologically active metabolite, lypressin or lysine-vasopressin. Once formed, lypressin is undergoes various peptidase-mediated metabolic pathways in body tissues. Terlipressin is not metabolized in the blood or plasma. Due to the ubiquitous nature of peptidases in body tissues, it is unlikely that the metabolism of terlipressin will be affected by disease state or other drugs.8

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Route of elimination

Less than 1% of terlipressin and <0.1% of lysine-vasopressin is excreted in urine in healthy subjects.8

Half-life

The terminal half-life of terlipressin was 0.9 hours and 3.0 hours for lysine-vasopressin.8

Clearance

The clearance of terlipressin was 27.4 L/hr and 318 L/hr for lysine-vasopressin. Clearance of terlipressin in HRS-1 patients increased with body weight, while body weight had no effect on the clearance of lysine-vasopressin.8

Adverse Effects
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Toxicity

There is no information available regarding the drug's LD50. While there is limited clinical experience with terlipressin overdose, manifestations are expected to be similar to the adverse reactions experienced with therapeutic doses. In case of an overdosage, initiate close monitoring of vital signs, electrolytes, and potential ischemic events and initiate appropriate symptomatic treatment.8

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Terlipressin.
AdenosineThe risk or severity of QTc prolongation can be increased when Adenosine is combined with Terlipressin.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Terlipressin.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Terlipressin.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Terlipressin.
AmantadineThe risk or severity of QTc prolongation can be increased when Amantadine is combined with Terlipressin.
AmifampridineThe risk or severity of QTc prolongation can be increased when Terlipressin is combined with Amifampridine.
AmiodaroneThe risk or severity of QTc prolongation can be increased when Terlipressin is combined with Amiodarone.
AmisulprideThe risk or severity of QTc prolongation can be increased when Terlipressin is combined with Amisulpride.
AmitriptylineThe risk or severity of QTc prolongation can be increased when Amitriptyline is combined with Terlipressin.
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Terlipressin acetate4U092XZF0KNot AvailableMLECZWUGJYWVAV-NSECCGHPSA-N
International/Other Brands
Glypressin (Ferring Pharmaceuticals) / Lucassin / Teripress (New Medicon Pharma)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TerlivazInjection, powder, lyophilized, for solution0.85 mg/5mLIntravenousMallinckrodt Hospital Products Inc.2022-09-14Not applicableUS flag

Categories

ATC Codes
H01BA04 — Terlipressin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
7Z5X49W53P
CAS number
14636-12-5

References

General References
  1. Pesaturo AB, Jennings HR, Voils SA: Terlipressin: vasopressin analog and novel drug for septic shock. Ann Pharmacother. 2006 Dec;40(12):2170-7. Epub 2006 Dec 5. [Article]
  2. Klein M, Weksler N, Borer A, Koyfman L, Kesslin J, Gurman GM: Terlipressin facilitates transport of septic patients treated with norepinephrine. Isr Med Assoc J. 2006 Oct;8(10):691-3. [Article]
  3. Leone M, Charvet A, Delmas A, Albanese J, Martin C, Boyle WA: Terlipressin: a new therapeutic for calcium-channel blockers overdose. J Crit Care. 2005 Mar;20(1):114-5. [Article]
  4. Matok I, Vard A, Efrati O, Rubinshtein M, Vishne T, Leibovitch L, Adam M, Barzilay Z, Paret G: Terlipressin as rescue therapy for intractable hypotension due to septic shock in children. Shock. 2005 Apr;23(4):305-10. [Article]
  5. Kam PC, Williams S, Yoong FF: Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia. 2004 Oct;59(10):993-1001. [Article]
  6. Kulkarni AV, Arab JP, Premkumar M, Benitez C, Tirumalige Ravikumar S, Kumar P, Sharma M, Reddy DN, Simonetto DA, Rao PN: Terlipressin has stood the test of time: Clinical overview in 2020 and future perspectives. Liver Int. 2020 Dec;40(12):2888-2905. doi: 10.1111/liv.14703. [Article]
  7. Cuzzo B, Padala SA, Lappin SL: Physiology, Vasopressin . [Article]
  8. FDA Approved Drug Products: TERLIVAZ (terlipressin) for injection, for intravenous use [Link]
Human Metabolome Database
HMDB0015569
PubChem Compound
72081
PubChem Substance
46504626
ChemSpider
65067
RxNav
57048
ChEBI
135905
ChEMBL
CHEMBL2135460
Therapeutic Targets Database
DAP000058
PharmGKB
PA164781020
Wikipedia
Terlipressin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionAcute Kidney Injury (AKI) / Liver Transplantation / NGAL / Terlipressin1
4CompletedPreventionCirrhosis of the Liver / Upper Gastrointestinal Hemorrhage1
4CompletedTreatmentAcute Variceal Haemorrhage1
4CompletedTreatmentBleeding / Varices, Esophageal1
4CompletedTreatmentCirrhosis of the Liver / Hematemesis / Melena / Portal Hypertension1
4CompletedTreatmentGastric and Esophageal Varices1
4CompletedTreatmentHemorrhage / Portal Hypertension / Varices, Esophageal1
4CompletedTreatmentVariceal Bleeding, Cirrhosis1
4CompletedTreatmentVasoconstrictor Choice on Acute Variceal Bleeding1
4Not Yet RecruitingTreatmentLiver Cirrhosis Portal1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SolutionIntravenous0.85 mg
Injection, powder, for solutionParenteral1 MG/5ML
SolutionIntravenous500 μg
Injection, solutionParenteral
Injection, powder, for solutionParenteral
Injection, powder, lyophilized, for solutionIntravenous0.86 mg
InjectionIntravenous
Injection, solutionIntravenous
Injection, powder, for solutionIntravenous
Injection, powder, for solutionIntravenous1 mg/8.5mL
Injection, powder, for solutionIntravenous1 mg
Injection, solutionIntravenous1 mg/8.5ml
Injection, powder, for solutionParenteral1 mg
SolutionIntravenous1 mg
Injection, solutionParenteral0.2 MG/ML
Injection, powder, for solution
Injection, solutionParenteral1 MG/8.5ML
Injection, solutionParenteral0.1 MG/ML
Injection, powder, lyophilized, for solutionIntravenous0.85 mg/5mL
Powder1 mg/1vial
Injection, solution1 mg/8.5ml
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility1 g/Lhttps://static.cymitquimica.com/products/01/pdf/sds-H-6604.pdf

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Vasopressin receptor activity
Specific Function
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system. Has been involved in social behavi...
Gene Name
AVPR1A
Uniprot ID
P37288
Uniprot Name
Vasopressin V1a receptor
Molecular Weight
46799.105 Da
References
  1. Hiroyama M, Wang S, Aoyagi T, Oikawa R, Sanbe A, Takeo S, Tanoue A: Vasopressin promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor in neonatal mice. Eur J Pharmacol. 2007 Mar 22;559(2-3):89-97. Epub 2006 Dec 29. [Article]
  2. Liedman R, Grant L, Igidbashian S, James I, McLeod A, Skillern L, Akerlund M: Intrauterine pressure, ischemia markers, and experienced pain during administration of a vasopressin V1a receptor antagonist in spontaneous and vasopressin-induced dysmenorrhea. Acta Obstet Gynecol Scand. 2006;85(2):207-11. [Article]
  3. Adikesavan NV, Mahmood SS, Stanley N, Xu Z, Wu N, Thibonnier M, Shoham M: A C-terminal segment of the V1R vasopressin receptor is unstructured in the crystal structure of its chimera with the maltose-binding protein. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 Apr 1;61(Pt 4):341-5. Epub 2005 Mar 24. [Article]
  4. Hammock EA, Lim MM, Nair HP, Young LJ: Association of vasopressin 1a receptor levels with a regulatory microsatellite and behavior. Genes Brain Behav. 2005 Jul;4(5):289-301. [Article]
  5. Aoyagi T, Birumachi J, Hiroyama M, Fujiwara Y, Sanbe A, Yamauchi J, Tanoue A: Alteration of glucose homeostasis in V1a vasopressin receptor-deficient mice. Endocrinology. 2007 May;148(5):2075-84. Epub 2007 Feb 15. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. FDA Approved Drug Products: TERLIVAZ (terlipressin) for injection, for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Vasopressin receptor activity
Specific Function
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system.
Gene Name
AVPR1B
Uniprot ID
P47901
Uniprot Name
Vasopressin V1b receptor
Molecular Weight
46970.345 Da
References
  1. Young WS, Li J, Wersinger SR, Palkovits M: The vasopressin 1b receptor is prominent in the hippocampal area CA2 where it is unaffected by restraint stress or adrenalectomy. Neuroscience. 2006 Dec 28;143(4):1031-9. Epub 2006 Oct 4. [Article]
  2. Volpi S, Liu Y, Aguilera G: Vasopressin increases GAGA binding activity to the V1b receptor promoter through transactivation of the MAP kinase pathway. J Mol Endocrinol. 2006 Jun;36(3):581-90. [Article]
  3. Wersinger SR, Caldwell HK, Christiansen M, Young WS 3rd: Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice. Genes Brain Behav. 2007 Oct;6(7):653-60. Epub 2006 Dec 20. [Article]
  4. Slusarz MJ, Gieldon A, Slusarz R, Ciarkowski J: Analysis of interactions responsible for vasopressin binding to human neurohypophyseal hormone receptors-molecular dynamics study of the activated receptor-vasopressin-G(alpha) systems. J Pept Sci. 2006 Mar;12(3):180-9. [Article]
  5. Jurkevich A, Berghman LR, Cornett LE, Kuenzel WJ: Characterization and immunohistochemical visualization of the vasotocin VT2 receptor in the pituitary gland of the chicken, Gallus gallus. Gen Comp Endocrinol. 2005 Aug;143(1):82-91. Epub 2005 Mar 23. [Article]
  6. FDA Approved Drug Products: TERLIVAZ (terlipressin) for injection, for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Vasopressin receptor activity
Specific Function
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.
Gene Name
AVPR2
Uniprot ID
P30518
Uniprot Name
Vasopressin V2 receptor
Molecular Weight
40278.57 Da
References
  1. Boson WL, Della Manna T, Damiani D, Miranda DM, Gadelha MR, Liberman B, Correa H, Romano-Silva MA, Friedman E, Silva FF, Ribeiro PA, De Marco L: Novel vasopressin type 2 (AVPR2) gene mutations in Brazilian nephrogenic diabetes insipidus patients. Genet Test. 2006 Fall;10(3):157-62. [Article]
  2. Slusarz MJ, Slusarz R, Ciarkowski J: Investigation of mechanism of desmopressin binding in vasopressin V2 receptor versus vasopressin V1a and oxytocin receptors: molecular dynamics simulation of the agonist-bound state in the membrane-aqueous system. Biopolymers. 2006 Apr 5;81(5):321-38. [Article]
  3. Bouley R, Hawthorn G, Russo LM, Lin HY, Ausiello DA, Brown D: Aquaporin 2 (AQP2) and vasopressin type 2 receptor (V2R) endocytosis in kidney epithelial cells: AQP2 is located in 'endocytosis-resistant' membrane domains after vasopressin treatment. Biol Cell. 2006 Apr;98(4):215-32. [Article]
  4. Yi X, Bouley R, Lin HY, Bechoua S, Sun TX, Del Re E, Shioda T, Raychowdhury MK, Lu HA, Abou-Samra AB, Brown D, Ausiello DA: Alix (AIP1) is a vasopressin receptor (V2R)-interacting protein that increases lysosomal degradation of the V2R. Am J Physiol Renal Physiol. 2007 May;292(5):F1303-13. Epub 2007 Feb 6. [Article]
  5. FDA Approved Drug Products: TERLIVAZ (terlipressin) for injection, for intravenous use [Link]

Drug created at June 13, 2005 13:24 / Updated at September 26, 2022 19:02