Mechanism of Action of Terlipressin in Hepatorenal Syndrome
Terlipressin is a synthetic vasopressin analogue that acts as a prodrug and direct agonist at vasopressin V1 receptors, with twice the selectivity for V1 versus V2 receptors, causing splanchnic vasoconstriction that reduces portal hypertension and increases effective arterial volume, thereby improving renal perfusion in patients with hepatorenal syndrome. 1
Primary Pharmacologic Mechanism
Terlipressin functions through a dual mechanism: it acts both as a prodrug that is converted to lysine-vasopressin by tissue peptidases cleaving N-terminal glycyl residues, and it has direct pharmacologic activity on its own 1
The drug demonstrates twice the selectivity for vasopressin V1 receptors compared to V2 receptors, which is critical for its therapeutic effect 1
V1 receptor stimulation occurs on smooth muscle vasculature of the splanchnic circulation, resulting in potent splanchnic vasoconstriction 2, 3
Hemodynamic Effects in Hepatorenal Syndrome
The fundamental therapeutic action is counteracting splanchnic arterial vasodilation, which is the primary pathophysiologic driver of hepatorenal syndrome 4
Splanchnic vasoconstriction leads to:
- Reduction in portal hypertension and decreased blood flow in portal vessels 1
- Increased effective arterial volume 1
- Increased mean arterial pressure (MAP), with maximum effect of approximately 16.2 mmHg occurring 1.2-2 hours post-dose 1
- Suppression of vasoconstrictor systems including plasma renin activity and norepinephrine 5
These hemodynamic changes improve renal perfusion by restoring effective arterial blood volume, reversing the renal vasoconstriction that characterizes hepatorenal syndrome 3, 5
Systemic Cardiovascular Response
Within 5 minutes of administration, terlipressin increases diastolic, systolic, and mean arterial pressure while decreasing heart rate (maximum decrease of 10.6 beats/minute) 1
These effects are maintained for at least 6 hours after dosing, supporting the every 4-6 hour dosing regimen 1
The increase in systemic vascular resistance is particularly pronounced in the splanchnic area, which is the target circulation in hepatorenal syndrome 3
Metabolic Pathway and Duration of Action
Terlipressin is metabolized by various tissue peptidases throughout the body, not in blood or plasma, making it unlikely to be affected by hepatic dysfunction or drug interactions 1
The terminal half-life is 0.9 hours for terlipressin and 3.0 hours for its active metabolite lysine-vasopressin 1
Less than 1% of terlipressin and <0.1% of lysine-vasopressin is excreted in urine, indicating predominantly tissue-based metabolism 1
Clinical Correlation with Renal Function Improvement
The improvement in circulatory function translates directly to renal benefit, with marked increases in glomerular filtration rate, renal plasma flow, and renal sodium excretion 4
The mechanism explains why terlipressin must be combined with albumin: albumin increases volaemia to counteract the decrease in cardiac output associated with hepatorenal syndrome, and provides antioxidant and anti-inflammatory properties 4
Studies demonstrate that terlipressin alone achieves only a 25% response rate versus 77% when combined with albumin, highlighting the importance of volume expansion alongside vasoconstriction 6
Important Mechanistic Considerations
The V1 receptor selectivity minimizes antidiuretic effects (which would be mediated by V2 receptors in renal tubules), focusing the therapeutic action on vasoconstriction 1, 2
The prodrug design provides a longer duration of action compared to native vasopressin, allowing for practical dosing intervals 1
A critical caveat: while terlipressin improves renal perfusion through systemic hemodynamic effects, recent evidence suggests hepatorenal syndrome is not purely functional, with components of direct tubular damage, meaning the mechanism addresses the primary but not sole pathophysiologic abnormality 4