Terlipressin
Also known as: triglycyl-lysine vasopressin, Glypressin, Lucassin, vasopressin prodrug
Synthetic vasopressin analogue / splanchnic vasoconstrictor — peptidomimetic prodrug; 12-amino-acid triglycyl-lysine vasopressin
What it is
Terlipressin is a prescription injectable medication used in hospital settings to treat two life-threatening complications of advanced liver disease: a sudden drop in kidney function called hepatorenal syndrome, and dangerous bleeding from dilated veins in the esophagus (varices). It is the only FDA-approved drug in the US specifically for hepatorenal syndrome-acute kidney injury.
The scientific side
terlipressin is a synthetic 12-amino-acid peptidomimetic prodrug of lysine-vasopressin ([8-Lys]-vasopressin, LVP) in which the N-terminus of vasopressin is protected by three glycine residues (triglycyl extension). After intravenous administration, this triglycyl moiety is cleaved enzymatically by endogenous peptidases at a controlled rate, generating the active moiety LVP over several hours. This prodrug design confers a longer effective half-life compared to synthetic arginine vasopressin (AVP), making terlipressin suitable for intermittent bolus dosing rather than continuous infusion — though accumulating evidence favors continuous infusion to reduce peak-concentration-related ischemic adverse effects. The active metabolite LVP exerts its principal pharmacological actions through selective agonism at vasopressin V1a receptors expressed on vascular smooth muscle cells of the splanchnic circulation. Activation of V1a receptors via Gq protein coupling stimulates phospholipase C, generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which triggers intracellular calcium release and protein kinase C activation, leading to smooth muscle contraction and vasoconstriction. In the setting of decompensated cirrhosis and portal hypertension, the splanchnic circulation undergoes pathological vasodilation driven by excess nitric oxide, prostacyclins, and bacterial translocation-related mediators. Splanchnic vasodilation reduces effective arterial blood volume (EABV), activates compensatory neurohumoral systems (renin-angiotensin-aldosterone, sympathetic nervous system), and critically reduces renal perfusion pressure — the central mechanism of hepatorenal syndrome-acute kidney injury (HRS-AKI). Terlipressin-induced splanchnic vasoconstriction increases systemic vascular resistance, improves mean arterial pressure, expands EABV, and reduces the hyperactivation of renal vasoconstrictive neurohumoral axes, thereby restoring glomerular filtration. In acute variceal hemorrhage, terlipressin reduces portal pressure by constricting the splanchnic vascular bed, lowering blood flow into the portal venous system and reducing intravariceal pressure, thus helping achieve hemostasis at the variceal bleeding site. Terlipressin also possesses modest V2 receptor agonist activity, which mediates antidiuretic effects at the renal collecting duct; this V2 activity is substantially lower than that of AVP, which partially explains why clinically meaningful hyponatremia is less frequent than with AVP, though it remains a documented adverse event. In critically ill patients outside cirrhosis, terlipressin has been investigated as a catecholamine-sparing vasopressor in vasodilatory shock, acting through a mechanism independent of adrenergic receptors, relevant in the emerging concept of decatecholaminization.
Class: Synthetic vasopressin analogue / splanchnic vasoconstrictor — peptidomimetic prodrug; 12-amino-acid triglycyl-lysine vasopressin
Administration & storage
- Administration
- Intravenous (IV) bolus injection — FDA-approved route for HRS-AKI; also standard for variceal hemorrhageContinuous intravenous infusion — investigated in multiple RCTs for both HRS-AKI and variceal hemorrhage; emerging evidence favors this route for reduced adverse eventsSubcutaneous administration — investigational only via analogue development (PHIN-214); direct SC terlipressin injection is not an approved or widely studied route
- Storage
- Lyophilized terlipressin should be stored at controlled room temperature (15–30°C / 59–86°F) protected from light and moisture, per manufacturer labeling. Reconstituted solution should be used immediately or stored at 2–8°C (refrigerated) for a limited period specified by the manufacturer. Terlipressin is susceptible to hydrolytic and oxidative degradation; elevated temperature, light exposure, and prolonged storage after reconstitution are associated with reduced potency. Ready-to-use solutions should follow manufacturer-specified storage conditions.
- Cautions
- Boxed Warning (US labeling): Respiratory failure — terlipressin can cause or worsen respiratory failure, particularly in patients with serum creatinine ≥5 mg/dL, severe ACLF, or pre-existing hypoxia; monitor oxygen saturation continuously and discontinue immediately if respiratory failure develops,Cardiovascular monitoring: Terlipressin causes systemic vasoconstriction beyond the splanchnic bed; monitor for cardiac arrhythmias (bradycardia is the most common; pooled North American phase III data showed cardiac AEs including bradycardia in terlipressin arm; PMID: 40704461), ischemic ECG changes, myocardial ischemia, and hypertensive crises,Peripheral and visceral ischemia: Severe and rare but documented adverse events include peripheral limb ischemia, skin necrosis, bowel ischemia, duodenal necrosis, and scrotal skin necrosis; discontinue immediately if signs of digital or limb ischemia develop,Hyponatremia: Terlipressin's partial V2 agonism can cause dilutional hyponatremia, including severe symptomatic hyponatremia (Na <120 mmol/L documented in case reports; PMID: 39144872); monitor serum sodium at baseline and frequently during treatment, particularly in patients with pre-existing hyponatremia or large-volume albumin co-infusion,Lactic acidosis: Terlipressin-induced widespread vasospasm can cause severe lactic acidosis and multi-organ dysfunction (case report documenting lactate 20 mmol/L and pH 6.97; PMID: 41809276); monitor lactate in patients with unexplained clinical deterioration during terlipressin therapy,Contraindicated in active respiratory failure; use with caution in patients with coronary artery disease, peripheral vascular disease, cerebrovascular disease, hypertension, or cardiac arrhythmias; these patient populations have elevated ischemic risk from V1a-mediated systemic vasoconstriction,Pregnancy and lactation: Terlipressin is not approved for use in pregnancy; limited data; vasopressin analogues can cause uterine contraction
Legal & regulatory status
Terlipressin (brand name Terlivaz) was approved by the US Food and Drug Administration on August 11, 2022, as the first and only FDA-approved treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI) in adults.…
Terlipressin is not included on the World Anti-Doping Agency (WADA) Prohibited List as of 2024–2025. It is a prescription vasoconstrictor used exclusively in hospital settings for life-threatening complications of…
Terlipressin has been approved in Canada for multiple indications related to portal hypertension, including acute esophageal variceal hemorrhage and hepatorenal syndrome. Canada approved terlipressin earlier than the…
What it's studied for
- Hepatorenal syndrome-acute kidney injury (HRS-AKI) — FDA-approved indication Phase III RCT (multiple) + FDA approval
- Acute esophageal variceal hemorrhage (AVH) — hemostasis and prevention of rebleed Phase III RCTs + systematic review + meta-analysis
- Prevention of hepatorenal syndrome and renal dysfunction in cirrhosis — secondary prophylaxis RCT + observational data
- Vasodilatory shock and septic shock — catecholamine-sparing adjunct (off-label/investigational) Meta-analysis of RCTs + narrative review
- Portal hypertension-related hyperdynamic circulation and ascites management in cirrhosis Phase I/II data + practice guidance
- Pharmacokinetic and chemical stability research — peptidomimetic degradation profiling Analytical chemistry / preclinical stability study
- Subcutaneous administration route — investigational analogue development informed by terlipressin's IV limitations Preclinical / Phase I investigational
Safety signals
- Respiratory failure
- Bradycardia and cardiac arrhythmias
- Peripheral and cutaneous ischemia / skin necrosis
- Hyponatremia (including severe symptomatic hyponatremia)
- Severe lactic acidosis and multi-organ dysfunction secondary to vasospasm
- Bowel and visceral ischemia (including duodenal necrosis)
- Systemic hypertension and elevated blood pressure
- Adverse events amplified when combined with targeted albumin infusion protocols
Frequently asked
Is terlipressin available in the United States?
Yes — terlipressin (brand name Terlivaz) received FDA approval in August 2022, becoming the first and only approved treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI) in the US. It is a prescription-only hospital-administered medication. It is not available over the counter or through compounding pharmacies for self-administration. Prior to 2022, it was widely used in Canada, Europe, and Asia for both HRS and variceal bleeding but was unavailable in the US. The US label covers HRS-AKI only; variceal hemorrhage remains an off-label use in the US, though it is an approved indication internationally.
What is the difference between terlipressin and vasopressin?
Terlipressin is a synthetic prodrug of lysine-vasopressin (LVP), not of arginine vasopressin (AVP, the endogenous human vasopressin). It has a triglycyl extension at the N-terminus that is slowly cleaved by enzymes in the body, releasing active LVP over several hours and giving terlipressin a longer effective duration of action than direct vasopressin or its analogue. This longer half-life allows intermittent bolus dosing (every 4–6 hours for variceal bleeding, or every 6 hours for HRS-AKI) rather than continuous infusion. Terlipressin is more selective for V1a (vasoconstrictor) receptors and has less V2 (antidiuretic) receptor activity than AVP, which partly accounts for its somewhat lower rate of hyponatremia.
What is hepatorenal syndrome and how does terlipressin treat it?
Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a severe and often fatal complication of advanced liver cirrhosis where the kidneys fail — not due to structural kidney damage, but because of profound reduction in blood supply. In cirrhosis, abnormal blood vessel dilation in the gut (splanchnic vasodilation) reduces the blood volume reaching vital organs including the kidneys, triggering an emergency hormonal response that severely constricts the kidney's blood vessels and shuts down kidney function. Terlipressin works by constricting the dilated gut blood vessels, which redirects blood flow back toward the kidneys, improves mean arterial blood pressure, and reverses the hormonal cascade that is starving the kidneys of blood. It is always used with intravenous albumin, which helps maintain blood volume.
How long does terlipressin treatment last for hepatorenal syndrome?
Per the FDA-approved Terlivaz prescribing information for HRS-AKI, treatment continues until the patient achieves confirmed HRS reversal — defined as two serum creatinine values below 1.5 mg/dL measured more than 2 hours apart — or for up to a maximum of 14 days. Treatment should be discontinued earlier if: (1) serum creatinine has not decreased by at least 25% by day 4; (2) confirmed HRS reversal is achieved; (3) the patient undergoes renal replacement therapy or liver transplantation; or (4) serious adverse events such as respiratory failure, severe ischemia, or severe hyponatremia develop. Your treating physician will determine the appropriate duration based on lab values and clinical response.
What are the most serious side effects of terlipressin?
The most serious adverse effects of terlipressin relate to its mechanism — it causes blood vessel constriction throughout the body, not just in the liver and gut. The US FDA has placed a Boxed Warning on terlipressin for respiratory failure, which can develop suddenly, particularly in patients with advanced liver failure or those with pre-existing lung problems. Other serious risks include: cardiac arrhythmias including slow heart rate (bradycardia); ischemia (loss of blood supply) to the hands, feet, skin, intestines, or heart; severe lactic acidosis caused by widespread vasospasm; and low sodium levels in the blood (hyponatremia). Terlipressin is only used under continuous hospital monitoring for these reasons. Any signs of chest pain, limb pain or discoloration, breathing difficulty, or confusion during treatment must be reported to medical staff immediately.
Can terlipressin be used for variceal bleeding in the US?
The FDA-approved indication for terlipressin (Terlivaz) in the US is specifically for hepatorenal syndrome-acute kidney injury (HRS-AKI) — not for variceal bleeding. However, terlipressin is approved and recommended for acute variceal hemorrhage in Canada, Europe, and many other countries, where it is considered a first-line vasoconstrictor therapy alongside endoscopy. In the US, octreotide is the standard vasoactive drug used for variceal bleeding. Using terlipressin for variceal bleeding in the US would be considered off-label. All decisions about specific medical treatment must be made by qualified healthcare providers based on individual patient circumstances.