Terlipressin

Terlipressin is a synthetic analog of vasopressin consisting of lysine vasopressin with a triglycyl modification at the N-terminus. This modification acts as a prodrug mechanism — the triglycyl residues are slowly cleaved by endopeptidases in the bloodstream, gradually releasing active lysine vasopressin. This slow conversion provides sustained pharmacological activity with a more stable pharmacokinetic profile than native vasopressin, allowing bolus intravenous dosing rather than continuous infusion.

Terlipressin preferentially activates vasopressin V1 receptors over V2 receptors, producing selective vasoconstriction of the splanchnic vascular bed. This reduces portal venous pressure and blood flow to varices while also increasing renal perfusion pressure through systemic vasoconstriction. In the kidneys, this results in improved renal blood flow and glomerular filtration rate, which is the basis for its use in hepatorenal syndrome (HRS).

In September 2022, terlipressin was approved by the FDA (marketed as Terlivaz) for the treatment of hepatorenal syndrome type 1 (HRS-1) — now termed HRS-acute kidney injury (HRS-AKI) — in adults. The CONFIRM trial demonstrated that terlipressin significantly improved renal function (as measured by the primary endpoint of verified HRS reversal) compared to placebo when used with albumin. HRS is a devastating complication of advanced liver disease with high mortality, and terlipressin represents the first FDA-approved pharmacotherapy for this condition.

Outside the United States, terlipressin has been used for decades for the management of acute variceal bleeding, where it reduces portal pressure and helps control hemorrhage. It has also been studied for septic shock as a vasopressor alternative, particularly in vasopressin-resistant or catecholamine-resistant shock states.