Terlipressin

Terlipressin is a synthetic vasopressin analogue and the first FDA-approved medication (approved September 2022) for hepatorenal syndrome with rapid reduction of kidney function (HRS-AKI). It acts as a prodrug that is cleaved in vivo to release lysine-vasopressin, producing potent splanchnic vasoconstriction and improving renal perfusion in the setting of advanced liver disease.

Terlipressin is a prodrug consisting of three glycine residues attached to lysine-vasopressin (N-triglycyl-8-lysine-vasopressin). Tissue peptidases cleave the N-terminal glycyl residues, releasing the active moiety lysine-vasopressin. Lysine-vasopressin binds to V1 receptors in splanchnic and peripheral vascular smooth muscle, causing potent vasoconstriction. In hepatorenal syndrome, the underlying pathology is severe splanchnic vasodilation driven by portal hypertension and circulatory dysfunction; by reversing this vasodilation, terlipressin reduces effective arterial blood volume depletion, suppresses the renin-angiotensin-aldosterone and sympathetic nervous systems, and restores renal perfusion. This mechanism is distinct from other vasopressors in its preferential splanchnic action and prolonged duration.

In the pivotal CONFIRM trial (Phase 3, 300 patients), 29% of terlipressin-treated patients achieved verified reversal of HRS-AKI versus 16% on placebo. It has been used in Europe and Asia for over two decades prior to FDA approval. A meta-analysis of multiple RCTs confirms superiority over albumin alone and comparable or superior outcomes versus norepinephrine. Risk of respiratory failure is a significant safety signal; patients with SBP below 82 mmHg or baseline hypoxia are at elevated risk.

Peptides commonly paired with Terlipressin for synergistic effects.