Terlipressin has Stood the Test of Time

Clinical Overview in 2020 and Future Perspectives

Anand V. Kulkarni; Juan Pablo Arab; Madhumita Premkumar; Carlos Benítez; Sowmya Tirumalige Ravikumar; Pramod Kumar; Mithun Sharma; Duvvuru Nageshwar Reddy; Douglas A. Simonetto; Padaki Nagaraja Rao

Disclosures

Liver International. 2020;40(12):2888-2905. 

In This Article

Pharmacology and Mechanism of Action of Terlipressin in Cirrhosis

Pharmacokinetics and Pharmacodynamics of Terlipressin

Terlipressin is a non-selective agonist of both V1 (smooth muscles of the arterial vasculature in the splanchnic region) and V2 receptors (collecting ducts of renal tubules).[9,10] Terlipressin was introduced as a safer congener to the existing vasopressin.[11] Terlipressin is a prodrug. The active form is lysine vasopressin.[12] The distribution half-life of terlipressin is 8 minutes.[12] This leads to a peak concentration approximately 10 minutes after intravenous administration. Terlipressin is cleaved by endothelial peptidases, resulting in slow release of the active drug, lysine vasopressin, over 4–6 hours.[13] The pharmacokinetics of terlipressin aid in intermittent intravenous dosing every 4–6 hours.[1] Terlipressin has a volume of distribution of 0.6–0.9 L/kg. A small percentage of the parent drug is excreted unchanged in the urine. The effects of terlipressin on various organs have been shown in detail in Figure 1. The approved indications for the use of terlipressin are HRS and acute variceal bleed (AVB). There are other conditions for which there is a lack of definitive evidence, and smaller trials have shown some benefit with terlipressin. However, more extensive randomised controlled trials are required before recommending terlipressin for such indications which are discussed in later sections.

Figure 1.

Effect of terlipressin on various systems. (A) Effect on the peripheral vascular system and the cardiovascular system: Terlipressin causes peripheral systemic vasoconstriction and leads to an increase in mean arterial pressure, an increase in systemic vascular resistance, a decrease in heart rate, cardiac output but without any effect on myocardial perfusion and stroke volume. (B) Effect on splanchnic circulation: Terlipressin counteracts the nitric oxide-mediated vasodilatation and causes splanchnic vasoconstriction leading to a decrease in portal venous blood flow. (C) Effect on hepatic haemodynamics: Terlipressin also reduces the hepatic arterial resistance and decreases the hepatic venous pressure gradient (HVPG). (D) Effect on renal circulation: Terlipressin reduces the renal arterial resistance and increases renal perfusion pressure. The cumulative effect of all these leads to an increase in effective circulatory volume, which counteracts the activation of the renin-angiotensin-aldosterone system (RAAS) and improves the hyperdynamic circulation

Splanchnic Circulation and Renal Haemodynamics in Cirrhosis

The portal pressure gradient (ΔP) is a product of the blood flow in splanchnic circulation (Q) and the resistance (R) to the flow across the hepatic vascular bed and the portosystemic collaterals, which is given by Ohm's law as ΔP = Q × R.[14] The structural distortion of the intrahepatic vasculature, as a consequence of fibrosis, scarring and microvascular thrombosis, rises the static component of intrahepatic vascular resistance. Furthermore, increased production of vasoconstrictors (mainly endothelins) and a deficient release of vasodilators (nitric oxide), in combination with an exaggerated response to vasoconstrictors and an impaired vasodilatory response of the hepatic vascular bed, are responsible for the increased dynamic component of intrahepatic vascular resistance.[15] The pressure exerted by increased intrahepatic vascular resistance on the portal venous system induces shear stress on the splanchnic vessels leading to the release of potent vasodilators such as nitric oxide (NO). Consequently, splanchnic arterial vasodilation ensues. This leads to pooling of blood in splanchnic circulation, affecting the systemic circulation by decreasing the mean arterial pressure (MAP) and effective arterial blood volume. Reduced effective circulating blood volume activates the neurohumoral systems causing sodium retention, water retention and an increase in cardiac output, which culminates in the hyperdynamic circulatory state.

Renal Circulation in Cirrhosis

The relationship between renal blood flow (RBF) and renal perfusion pressure (RPP) can be explained by a sigmoid curve.[16] RBF is dependent on the RPP, which is influenced by the sympathetic nervous system (SNS).[16] Renal autoregulation effectively operates at a renal perfusion pressure of 65–75 mm Hg, and renal blood flow decreases in proportion to renal perfusion pressure below this critical threshold. SNS stimulation proportionately increases with worsening liver disease. This leads to a rise in norepinephrine levels and shifts the curve to the right and downwards, decreasing RBF at the same renal plasma flow (RPF) in cirrhotics with ascites. The curve shifts further to the right as patients develop refractory ascites and HRS (Figure 2).[16] The mean glomerular filtration rate (GFR) is 82.9 mL/min/1.73 m2, with a corresponding RPF of 229.9 mL/min/1.73 m2 in patients without ascites. While the mean GFR is 82.3 mL/min/1.73 m2 with RPF of 344.1 mL/min/1 in diuretic-sensitive ascites, but the GFR is reduced to 36.5 mL/min/1.73 m2 with RPF of 133.6 mL/min/1.73 m2 in diuretic resistant ascites.[17] As the liver cirrhosis progresses, SNS is activated, which increases the RPP, but the RBF/GFR decline gradually. Hence, renal dysfunction is common in cirrhotics at later stages.

Figure 2.

Curve A: In patients, without ascites, the renal blood flow directly correlates with renal perfusion pressure as depicted by the smooth sigmoid curve. Curve B: In diuretic responsive ascites, the curve shifts to the right caused by the excessive sympathetic nervous system (SNS) activity. Curve C: In diuretic resistant ascites, the curve further shifts right and downward, and the renal blood flow decreases at the same renal plasma flow with increasing renal perfusion pressure. Curve D: In hepatorenal syndrome, the hyperactivated SNS flattens the sigmoid curve leading to hypoperfusion of the kidneys. (Graph modified from Stadlbauer V et al Gastroenterology. 2008;134(1):115 with permission)

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