Terlipressin

證據等級: L5

預測適應症: 7 個

Terlipressin: From Portal Hypertension to Pulmonary Hypertension

One-Sentence Summary

Terlipressin is a synthetic vasopressin analogue with established use in portal hypertension complications — including acute variceal hemorrhage and hepatorenal syndrome (HRS) — acting via V1 receptor-mediated splanchnic vasoconstriction to reduce portal venous inflow. The TxGNN model’s highest-ranked prediction is open-angle glaucoma (score 99.78%), but this indication has zero supporting evidence and is assessed as a graph-network false positive; the most clinically meaningful prediction is Pulmonary Hypertension (rank #3, score 99.56%), supported by 4 clinical trials and 20 publications — primarily hemodynamic studies in cirrhosis-associated pulmonary hypertension and neonatal rescue cases.

Quick Overview

Item	Content
Original Indication	Portal hypertension (variceal hemorrhage, hepatorenal syndrome)
Predicted New Indication	Pulmonary Hypertension
TxGNN Prediction Score	99.56% (Rank #3)
Evidence Level	L4
US Market Status	Not Marketed (0 active licenses in evidence pack)
Number of NDAs	0
Recommended Decision	Hold (Research Question)

Why is This Prediction Reasonable?

Terlipressin is a triglycyl prodrug of lysine-vasopressin that is enzymatically cleaved in vivo to release active lysine-vasopressin. Its primary pharmacological action is agonism at V1a receptors on vascular smooth muscle, inducing potent splanchnic vasoconstriction. This reduces mesenteric blood flow and portal venous inflow, thereby lowering portal pressure — the basis for its clinical use in variceal bleeding and hepatorenal syndrome. Detailed MOA data was not available in this evidence pack; the above is inferred from the drug’s pharmacological class and the clinical literature retrieved.

The link to pulmonary hypertension is most coherent in the context of portopulmonary hypertension (PoPH) — a recognized WHO Group 1.4 subtype that develops as a complication of portal hypertension, in which portal-to-pulmonary shunting of vasoactive mediators drives pulmonary vascular remodeling. In this subtype, reducing portal pressure pharmacologically can indirectly alleviate right-heart afterload. Small hemodynamic studies (Kalambokis et al., 2004, 2008, 2012) demonstrated that terlipressin selectively reduces pulmonary vascular resistance (PVR) in cirrhotic patients with elevated PVR, while simultaneously decreasing portal pressure — a dual benefit not seen with conventional vasoconstrictors such as norepinephrine, which can worsen PH.

A distinct body of evidence comes from neonatal medicine, where terlipressin has been used as rescue therapy for persistent pulmonary hypertension of the newborn (PPHN) in congenital diaphragmatic hernia and sepsis-related cases. Here the proposed mechanism differs: vasopressin receptor activation may support systemic blood pressure without increasing PVR, thereby maintaining right-to-left pressure gradients. One RCT in adult cardiac surgery patients (Abdelazziz & Abdelhamid, 2019) found terlipressin did not increase mean pulmonary artery pressure (MPAP) when used to counteract milrinone-induced hypotension, unlike norepinephrine. Collectively, this evidence positions terlipressin as a vasopressor with favorable pulmonary hemodynamic properties in specific secondary PH contexts — but it does not support use in primary or idiopathic PAH, where systemic vasoconstriction may be detrimental.

Clinical Trial Evidence

All retrieved trials are graded C relevance (indirect) — none specifically investigates terlipressin as a treatment for pulmonary hypertension.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03584087	Phase 4	Completed	74	Terlipressin vs. standard of care after endoscopic variceal ligation in acute variceal hemorrhage; completed trial providing portal pressure reduction data with systemic hemodynamic readouts
NCT06027970	Phase 3	Unknown	165	Continuous terlipressin infusion post-EVL for acute variceal hemorrhage; cardiopulmonary hemodynamic safety data may be extractable as secondary outcome
NCT05315557	N/A	Unknown	100	Vasopressin vs. terlipressin as second-line vasopressor in cirrhotic patients with septic shock; provides comparative pulmonary safety profiling across both agents in a high-risk population
NCT06256432	Phase 2	Active, not recruiting	54	Ambrisentan (ERA approved for PAH) in hepatorenal syndrome — terlipressin used as background therapy; highlights the mechanistic overlap between PoPH and HRS management, with ERA as potential combination partner

Literature Evidence

PMID	Year	Type	Journal	Key Findings
30971593	2019	RCT	Ann Cardiac Anaesthesia	Terlipressin vs. norepinephrine to reverse milrinone-induced hypotension in cardiac surgery patients with pre-existing PH; terlipressin restored systemic BP without increasing PVR or MPAP — unlike norepinephrine
22893473	2012	Hemodynamic observational	Hepatobiliary Pancreatic Dis Int	Single terlipressin dose (2 mg IV) reduced PVR and improved pulmonary hemodynamics in 7 cirrhotic patients with PH presenting with variceal bleeding or HRS; PVR decreased from 186.5 to 158.8 dyne·s·cm⁻⁵
21733953	2012	Hemodynamic study	Angiology	Terlipressin selectively reduced PVR in cirrhosis patients with elevated PVR (>120 dyne·s·cm⁻⁵) but not in those with normal PVR; supports a differential vasodilatory effect on pulmonary vs. systemic vasculature in PH-subset
18280605	2008	Case report	J Hepatology	Significant reduction in pulmonary arterial pressure after 1-week terlipressin treatment in a cirrhotic patient with moderate-to-severe portopulmonary hypertension; faster onset than prostacyclin analogues or endothelin receptor antagonists
15259082	2004	Observational	World J Gastroenterology	Echocardiographic assessment showing terlipressin reduced systolic pulmonary artery pressure in cirrhotic patients; among the earliest reports linking terlipressin to pulmonary pressure reduction
34179513	2021	Systematic review protocol	BMJ Paediatrics Open	Protocol for systematic review of vasopressin/terlipressin in preterm neonates with hypotension or persistent PH; acknowledges increasing off-label use and calls for formal evidence synthesis
32999121	2020	Case report	Indian Pediatrics	Terlipressin rescue therapy for refractory PPHN and shock in a preterm infant; pulmonary vasodilatory effect achieved where inhaled NO and other therapies failed
21292065	2011	Case report	J Pediatric Surgery	Terlipressin as rescue in neonatal refractory PPHN with congenital diaphragmatic hernia; rationale based on V1 receptor analogy to vasopressin’s known pulmonary vasodilatory mechanism
23128058	2012	Case report	J Perinatology	Asphyxiated septic infant with PH and catecholamine-resistant hypotension; terlipressin addition reduced pulmonary artery pressures on echocardiographic reassessment within 10 minutes
19624374	2009	Case series	Paediatric Anaesthesia	Role of terlipressin in severe PH complicating congenital diaphragmatic hernia in neonates; supports a distinct neonatal PPHN use-case as part of rescue vasopressor strategy

Safety Considerations

Please refer to the package insert for safety information.

No structured warning, contraindication, or drug-drug interaction data was available in this evidence pack. Based on the pharmacological class (vasopressin V1 agonist), clinical teams should be alert to: systemic vasoconstriction with risk of peripheral and mesenteric ischemia; bradycardia and cardiac arrhythmia; hyponatremia (ADH-like antidiuretic effect); and potential worsening of pulmonary hypertension in non-portal contexts. Formal safety assessment requires review of the prescribing information.

Conclusion and Next Steps

Decision: Hold (Research Question)

Rationale: The evidence base for terlipressin in pulmonary hypertension is mechanistically plausible but confined to secondary PH in cirrhosis (portopulmonary hypertension) and neonatal rescue cases — there are no prospective trials designed to test terlipressin as a PH-specific therapy, and none of the four retrieved clinical trials targets PH as the primary outcome. The signal is sufficient to formulate a research question, but not to support a development decision. Critically, the TxGNN top-ranked predictions (open-angle glaucoma, primary hereditary glaucoma, kyphoscoliotic heart disease, esotropia) all score L5 with zero supporting evidence and are assessed as graph-network false positives arising from non-specific vascular regulation node co-activation.

To proceed, the following is needed:

Define the target PH subtype: portopulmonary hypertension (PoPH, WHO Group 1.4) is the most mechanistically justified sub-indication and should be scoped separately from idiopathic PAH
Commission a formal hemodynamic feasibility study in PoPH patients with pulmonary artery catheterization as the primary measurement endpoint
Retrieve and review full mechanism of action data from DrugBank (DG002 remediation)
Obtain Taiwan FDA / target-market prescribing information to complete safety pre-screening (DG001 remediation)
Verify current regulatory status: Terlipressin (Terlivaz®) received US FDA approval in 2022 for HRS-1; this may not be reflected in the evidence pack’s 0-license readout and should be confirmed before any US-market development planning
Assess route-of-administration compatibility for a pulmonary hypertension indication (current IV formulation vs. inhaled/alternative delivery)
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.