Mechanism of Action of Terlipressin in Hepatorenal Syndrome
Terlipressin is a synthetic vasopressin analogue that acts as a prodrug and direct V1 receptor agonist, causing selective splanchnic vasoconstriction that reverses the pathophysiologic cascade of hepatorenal syndrome by reducing portal hypertension, increasing effective arterial volume and mean arterial pressure, which secondarily improves renal perfusion and glomerular filtration rate. 1, 2
Primary Pharmacologic Mechanism
Terlipressin has twice the selectivity for vasopressin V1 receptors versus V2 receptors, acting both as a prodrug for lysine-vasopressin and having direct pharmacologic activity on its own 1
The drug stimulates V1 receptors located on smooth muscle vasculature of the splanchnic circulation, resulting in potent splanchnic vasoconstriction 3, 4
Terlipressin is metabolized by tissue peptidases through cleavage of N-terminal glycyl residues, releasing the pharmacologically active metabolite lysine-vasopressin with a terminal half-life of 0.9 hours for terlipressin and 3.0 hours for lysine-vasopressin 1, 2
Hemodynamic Effects in Hepatorenal Syndrome
The primary therapeutic effect is reduction of portal hypertension through decreased portal venous inflow, which is the underlying driver of splanchnic vasodilation in cirrhosis 2
Terlipressin increases mean arterial pressure by an estimated maximum of 16.2 mmHg, with effects evident within 5 minutes and maintained for at least 6 hours after dosing 1, 2
The drug causes systemic vasoconstriction with increased systemic vascular resistance, particularly in the splanchnic area, resulting in decreased portal pressure and pressure in esophageal varices 4
Secondary Renal Effects
Improved renal perfusion occurs as a secondary effect of correcting the circulatory dysfunction, not through direct renal vasodilation 2
The mechanism involves restoration of effective arterial blood volume by reversing the arterial underfilling caused by mesenteric vasodilation, which then relieves compensatory renal vasoconstriction 4, 5
This leads to increased renal blood flow, improved glomerular filtration rate, and enhanced renal sodium excretion 2, 6
Circulatory Function Improvement
Treatment results in remarkable improvement in circulatory function with suppression of vasoconstrictor systems activity, including decreased plasma renin activity and plasma norepinephrine levels 5
The drug increases effective arterial volume and mean arterial pressure, reversing the hyperdynamic circulatory state characteristic of advanced cirrhosis 1, 2
Clinical Pharmacodynamics
After a single 0.85 mg dose, increases in diastolic, systolic, and mean arterial pressure are evident within 5 minutes, with maximum effects occurring at 1.2 to 2 hours post-dose 1
Heart rate decreases by an estimated maximum of 10.6 beats/minute as a compensatory response to increased blood pressure 1
The antidiuretic activity through V2 receptors in renal tubules is minimal due to the drug's preferential V1 selectivity 3
Important Mechanistic Considerations
Terlipressin has a significantly longer duration of action and fewer side effects compared to vasopressin, making it clinically superior for sustained treatment 2
The ubiquitous nature of tissue peptidases means metabolism is unlikely to be affected by disease state or drug interactions 1
Less than 1% of terlipressin and <0.1% of lysine-vasopressin is excreted in urine, with clearance primarily through tissue metabolism 1