Mechanism of Action of Terlipressin in Liver Disease with Renal Impairment
Terlipressin is a synthetic vasopressin analogue that acts as a prodrug and direct V1 receptor agonist, reversing the pathophysiology of hepatorenal syndrome by causing selective splanchnic vasoconstriction, which increases effective arterial blood volume, mean arterial pressure, and subsequently improves renal perfusion and glomerular filtration rate. 1, 2
Primary Pharmacologic Mechanism
Terlipressin has twice the selectivity for vasopressin V1 receptors versus V2 receptors, located on vascular smooth muscle, mediating vasoconstriction 1, 3
The drug functions both as a prodrug for lysine-vasopressin and as a pharmacologically active compound itself, with tissue peptidases cleaving N-terminal glycyl residues to release the active metabolite lysine-vasopressin 1, 4
Terlipressin has a terminal half-life of 0.9 hours, while its active metabolite lysine-vasopressin has a half-life of 3.0 hours, providing sustained therapeutic effect with fewer side effects compared to native vasopressin 2, 1
Hemodynamic Effects in Hepatorenal Syndrome
The fundamental pathophysiology of hepatorenal syndrome involves extreme splanchnic vasodilation causing decreased effective arterial blood volume, which triggers renal vasoconstriction and decreased glomerular filtration rate. 5
Terlipressin causes selective vasoconstriction of the markedly dilated splanchnic vascular bed, reducing portal venous inflow and portal pressure 5, 2
This splanchnic vasoconstriction increases effective arterial volume and mean arterial pressure by an average of 16.2 mmHg, with maximum effect occurring 1.2 to 2 hours post-dose 1, 2
The increase in effective arterial volume improves renal perfusion pressure as a secondary effect, leading to increased renal blood flow, improved glomerular filtration rate, and enhanced renal sodium excretion 2, 5
Hemodynamic changes are evident within 5 minutes of administration and maintained for at least 6 hours, with concurrent decrease in heart rate by approximately 10.6 beats/minute 1
Reversal of Hepatorenal Syndrome Pathophysiology
In cirrhosis with portal hypertension, terlipressin counteracts the vasodilated state by reducing portal flow and pressure, addressing the underlying driver of splanchnic vasodilation 5, 3
The drug improves circulatory function by antagonizing the activation of vasoactive systems (sympathetic nervous system and renin-angiotensin-aldosterone system) that cause renal vasoconstriction in hepatorenal syndrome 5
Treatment results in progressive reduction in serum creatinine, increase in arterial pressure, increase in urine volume, and increase in serum sodium concentration over a median time of 14 days 5
Albumin Synergy
Albumin must be administered concurrently with terlipressin to optimize efficacy, as terlipressin alone achieves only 25% response rate versus 77% with combination therapy 6, 5
The rationale for albumin co-administration is to fill the central circulation and enhance the effects of splanchnic vasoconstriction on improving renal blood flow, though this is likely achieved after 1-2 days 5
Albumin may have additional effects beyond volume expansion by attenuating systemic inflammatory responses, though the exact mechanisms remain uncertain 5
Clinical Efficacy Outcomes
Terlipressin improves renal function in 40-50% of patients with type 1 hepatorenal syndrome, with response characterized by serum creatinine decreasing below 1.5 mg/dL 5
Even partial reductions in serum creatinine are beneficial, with every 1 mg/dL drop associated with a 27% reduction in relative risk for mortality 5, 7
Treatment improves short-term survival and decreases need for renal replacement therapy, though it does not impact the underlying liver disease 5