Terlipressin

Contents

Overview

Terlipressin is a synthetic vasopressin analogue with prolonged action, used primarily in two hepatological emergencies: hepatorenal syndrome (HRS) and acute variceal haemorrhage. It acts on V1 receptors in vascular smooth muscle to produce splanchnic vasoconstriction, reducing portal hypertension and its complications. It is one of the few pharmacological interventions with evidence of improving survival in HRS.

Pharmacology

Structure: Terlipressin is a prodrug of lysine vasopressin (LVP). It consists of three glycine residues attached to the N-terminus of LVP. These are cleaved by endogenous peptidases, producing LVP with a prolonged duration of action compared with the parent compound.

Receptor profile:

  • V1 receptors: dominant effect — vascular smooth muscle contraction, particularly in the splanchnic, renal, and skin circulations. V1 stimulation also contracts myometrium.
  • V2 receptors: minor effect — antidiuretic action at the collecting duct. Much less than vasopressin.
  • Oxytocin receptors: minor effect.

The relative selectivity for V1 over V2 receptors distinguishes terlipressin from vasopressin. This means terlipressin has less antidiuretic effect and a lower risk of hyponatraemia in most clinical contexts, though hyponatraemia remains a clinically significant adverse effect.

Pharmacokinetics:

  • Half-life of terlipressin: approximately 6 hours (prodrug); LVP half-life is shorter (~2 hours)
  • Administered as IV bolus (intermittent dosing) or continuous infusion
  • No significant hepatic metabolism — not dose-adjusted in liver disease
  • Renal clearance

Clinical Indications

  1. Hepatorenal syndrome (HRS type 1 / HRS-AKI)
  2. Acute variceal haemorrhage (oesophageal and gastric varices)
  3. Refractory septic shock (off-label, now largely superseded by vasopressin)

Hepatorenal Syndrome

Pathophysiology of HRS

Cirrhosis leads to portal hypertension and splanchnic vasodilation mediated by nitric oxide, prostacyclin, and endocannabinoids. This reduces effective arterial blood volume. Baroreceptor-mediated activation of the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and ADH secretion follows, causing intense renal vasoconstriction and sodium/water retention.

HRS is the extreme of this haemodynamic dysfunction: renal blood flow is critically reduced, causing AKI in the absence of structural renal pathology. The kidneys are structurally normal — this is confirmed by recovery of renal function after liver transplantation.

The 2015 ICA (International Club of Ascites) criteria define HRS-AKI as:

  • Cirrhosis with ascites
  • AKI (creatinine rise ≥26.5 µmol/L in 48 hours, or ≥50% rise from baseline within 7 days)
  • No response after 48 hours of diuretic withdrawal and volume expansion with albumin (1 g/kg/day × 2 days)
  • Absence of shock
  • No use of nephrotoxic drugs
  • No structural kidney disease (no proteinuria >500 mg/day, no haematuria >50 RBC/HPF, normal renal ultrasound)

Treatment with Terlipressin

Terlipressin reverses splanchnic vasodilation, improving renal perfusion and creatinine without structural repair. It is given with albumin:

Terlipressin dose:

  • IV bolus: 0.5–1 mg every 4–6 hours; can increase to 2 mg every 4–6 hours if creatinine does not fall by 25% within 48 hours
  • Continuous infusion: 2–12 mg/24 hours; generally preferred for better tolerability

Albumin: 20–40 g/day IV (maintains oncotic pressure and further expands plasma volume)

The CONFIRM trial (Boyer et al., NEJM 2021) was a Phase 3 randomised placebo-controlled trial of terlipressin plus albumin vs albumin alone in HRS-AKI. Terlipressin significantly increased HRS reversal (29.1% vs 15.8%) and RRT-free survival at day 30. This confirmed an improvement in patient-relevant outcomes beyond biomarker change.

Continue treatment for up to 14 days; stop if creatinine rises after initial response, renal function has fully recovered, or adverse effects occur.

Liver transplantation is the definitive treatment for cirrhosis and HRS. Terlipressin serves as a bridge.

Variceal Haemorrhage

Portal hypertension causes the development of portosystemic collaterals, including oesophageal and gastric varices. Variceal rupture causes massive upper GI haemorrhage.

Terlipressin reduces portal pressure by splanchnic vasoconstriction, reducing blood flow through the portal circulation. It is more effective than vasopressin alone because of its longer duration of action and favourable side effect profile.

Dose for variceal haemorrhage:

  • 2 mg IV bolus every 4 hours for the first 48 hours
  • Then 1 mg every 4 hours for up to 5 days total

Terlipressin is started immediately on presentation, before or simultaneously with endoscopy. It reduces active bleeding, facilitates endoscopic haemostasis, and reduces early rebleeding.

Combined with endoscopic band ligation (primary treatment for oesophageal varices), terlipressin reduces 42-day mortality compared with either alone in some studies.

Adjuncts: broad-spectrum antibiotics (norfloxacin or ceftriaxone) reduce bacterial infections and rebleeding in variceal haemorrhage.

Adverse Effects

Adverse effects relate primarily to V1-mediated vasoconstriction:

Ischaemic complications: Peripheral ischaemia (pale, cyanotic digits, skin necrosis), mesenteric ischaemia, myocardial ischaemia. These are the most serious adverse effects and can be life-threatening.

Risk factors for ischaemic complications: pre-existing peripheral vascular disease, coronary artery disease, atrial fibrillation, septic shock co-existing with HRS.

Contraindications: severe peripheral vascular disease, ischaemic heart disease, cardiac arrhythmias, pregnancy (uterine contraction), severe asthma (bronchoconstriction).

Hyponatraemia: From V2-mediated antidiuretic effect; less pronounced than with vasopressin but still clinically relevant. Monitor sodium regularly.

Hypertension and bradycardia: Reflex bradycardia from vasoconstriction; hypertension from V1 effect on systemic vasculature.

Skin necrosis: From peripheral vasoconstriction, particularly at injection sites or in distal extremities.

Abdominal pain and diarrhoea: From intestinal smooth muscle contraction.

Monitor: daily examination of extremities, ECG, sodium, urine output.

Viva Questions

How does terlipressin work in hepatorenal syndrome and what is the evidence for its use?

Hepatorenal syndrome arises from severe splanchnic vasodilation in cirrhosis, which reduces effective arterial volume and triggers intense renal vasoconstriction. Terlipressin acts on V1 receptors in splanchnic vascular smooth muscle, reversing this vasodilation. Splanchnic vasoconstriction reduces portal inflow, lowers portal pressure, and improves effective systemic blood volume, which in turn reduces the baroreceptor-mediated stimulus for renal vasoconstriction. Renal perfusion improves and creatinine falls. Terlipressin is given alongside IV albumin, which provides additional volume expansion and plasma oncotic support. Evidence comes from multiple randomised trials and meta-analyses. The CONFIRM trial (Boyer et al., NEJM 2021) was the largest Phase 3 randomised trial in HRS-AKI: terlipressin plus albumin achieved HRS reversal in 29% vs 16% with albumin alone, and improved RRT-free survival at 30 days. Terlipressin is now first-line pharmacological therapy for HRS-AKI in patients without contraindications, pending liver transplantation.

What are the contraindications and adverse effects of terlipressin?

Terlipressin's principal adverse effects relate to generalised V1-mediated vasoconstriction. Peripheral ischaemia is the most clinically significant — fingers and toes may become pale or cyanotic, and in severe cases skin necrosis and gangrene can occur. Mesenteric ischaemia presents with abdominal pain out of proportion to examination. Myocardial ischaemia can occur in patients with coronary artery disease. Reflex bradycardia and hypertension are common. Hyponatraemia results from residual V2 antidiuretic activity. Absolute contraindications include severe peripheral vascular disease, ischaemic heart disease, significant arrhythmias, pregnancy (uterine contraction causing preterm labour), and severe asthma. Relative contraindications include any condition where generalised vasoconstriction would be harmful. In clinical practice, patients with HRS are often profoundly vasodilated and have low systemic vascular resistance — terlipressin is usually haemodynamically well tolerated in this population despite its vasoconstrictor properties. Careful daily monitoring of peripheral circulation, ECG, sodium, and urine output is essential during treatment.

How does terlipressin differ from vasopressin in its clinical applications and pharmacology?

Terlipressin and vasopressin both act on vasopressin receptors, but with different receptor selectivity and pharmacokinetic profiles. Vasopressin has more balanced V1 and V2 activity, making it both a potent vasoconstrictor and a powerful antidiuretic hormone. In septic shock, vasopressin is used at low doses (0.03–0.04 units/min) to supplement noradrenaline, exploiting its V1 vasoconstriction while the V2 antidiuretic effect is less clinically significant at these doses. Terlipressin is a prodrug cleaved to lysine vasopressin, with greater relative V1 selectivity and a longer duration of action. Its longer half-life allows intermittent bolus dosing, whereas vasopressin requires continuous infusion due to its very short half-life (10–20 minutes). Terlipressin is licensed for HRS and variceal haemorrhage; vasopressin is used in vasodilatory shock and as an adjunct in cardiac arrest. The choice between them in clinical practice is driven by indication, availability, and local guidelines. In the VANISH trial, vasopressin was compared with noradrenaline as a first-line vasopressor in septic shock — there was no mortality difference, but vasopressin was associated with reduced RRT requirements in the pre-specified subgroup of less severe sepsis.