Glypressin Mechanism of Action

Pharmacotherapeutic group: Posterior pituitary lobe hormones (vasopressin and analogues). ATC code: H01BA04.
Pharmacology: Pharmacodynamics: Terlipressin (Triglycyl-Lysine-Vasopressin) is a synthetic analogue of the natural posterior pituitary hormone vasopressin.
Terlipressin is a pro-drug with partial, intrinsic activity by itself. Terlipressin is transformed into the fully active metabolite lysine-vasopressin (LVP) by enzymatic cleavage. Doses of 1 and 2 mg terlipressin acetate effectively reduce the portal venous pressure and produce marked vasoconstriction. The lowering of portal pressure and azygos blood flow is dependent on dose. The effect of the low dose is reduced after 3 hours, while haemodynamic data show that 2 mg terlipressin acetate is more effective than 1 mg with a sustained effect throughout the treatment period of 4 to 6 hours.
Bleeding oesophageal varices: The pathophysiology of bleeding oesophageal varices is caused by the haemodynamic changes induced by portal hypertension leading to redirection of blood flow to blood vessels in the walls (lamina propria, submucosa) of the upper gastric and lower oesophageal regions resulting in the development of oesophageal varices. Terlipressin and its metabolites exert their effects via the vasopressin-1a receptor in vascular smooth muscle to induce splanchnic arterial vasoconstriction which results in a decrease of the portal pressure. Consequently, an improvement of the systemic circulatory function and redistribution of the effective arterial blood volume is observed.
Hepatorenal syndrome: The pathophysiology of type 1 hepatorenal syndrome is caused by the haemodynamic changes induced by portal hypertension seen in advanced cirrhosis. Terlipressin and its metabolites exert their effects via the vasopressin-1ɑ receptor in vascular smooth muscle to induce splanchnic arterial vasoconstriction which results in a decrease of the portal pressure. Consequently, an improvement of the systemic circulatory function and redistribution of the effective arterial blood volume is observed. Lowering of portal pressure together with the improved systemic circulation leads to the suppression of the activity of the renin-angiotensin system and sympathetic nervous system, which are major triggers of excessive renal vasoconstriction, causing type 1 hepatorenal syndrome.
Clinical efficacy and safety: Continuous intravenous infusion versus intravenous boluses in the treatment of type 1 hepatorenal syndrome in patients with cirrhosis: The safety of continuous intravenous infusion of terlipressin has been compared with intravenous bolus in an open-label randomised controlled multicentre trial. Seventy-eight patients with type 1 hepatorenal syndrome were randomly assigned to either continuous intravenous infusion at the initial dose of 2 mg/day or intravenous boluses of terlipressin at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups. The primary endpoint was defined as the prevalence of treatment-related adverse events (AEs) between the two groups. Both the total rate of treatment-related AEs as well as severe treatment-related AEs were lower in the continuous infusion group than in the bolus group (all treatment-related AEs: 12/34 patients (35%) vs 23/37 patients (62%), p<0.025. Severe treatment-related AEs: 7/34 patients (21%) vs 16/37 patients (43%); p<0.05). The rate of response to terlipressin was not statistically significantly different between the continuous infusion and bolus groups (76% vs 65%). The probability of 90-day transplant-free survival was not significantly different between the continuous infusion group and the bolus group (53% vs 69%).
Pharmacokinetics: The pharmacokinetics of terlipressin follows a two-compartment model with a rapid distribution phase.
Absorption: Terlipressin is administered by the intravenous route resulting in instant systemic exposure.
Distribution: In patients with liver cirrhosis with or without hepatorenal syndrome the mean distribution volume was reported in the range 0.2 to 0.5 l/kg in two clinical trials.
Biotransformation: The concentration of the active metabolite, lysine-vasopressin, starts to increase approximately 30 minutes after bolus administration of terlipressin and peak levels are reached between 60 and 120 minutes after administration of terlipressin.
Elimination: The terminal elimination half-life of terlipressin is approximately 40 minutes in patients with liver cirrhosis with and without hepatorenal syndrome and the mean clearance was reported in the range 5 to 9 ml/kg/min in two clinical trials.
Linearity: Terlipressin demonstrated a dose-dependent and approximate proportional increase in total exposure (AUC) after single IV injections to healthy subjects (n=2-14 subjects per dose group) in a dose range between 5 and 30 μg/kg.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of single- and repeat-dose toxicity, and genotoxicity. At dosages relevant to humans, the only effects observed in animals were those attributable to the pharmacological activity of terlipressin.
No pharmacokinetic data are available from animals but as the route of administration was intravenous, systemic exposure at multiples of the maximum human dosages can be assumed for the animal studies.
An embryo-fetal study in rats demonstrated no adverse effects of terlipressin, but in rabbits abortions occurred, probably related to maternal toxicity, and there were ossification anomalies in a small number of fetuses and a single isolated case of cleft palate.
In a rat fertility study, mating of terlipressin-treated males with untreated females had no effect on the number of matings and frequency of insemination but led to decreased post-natal litter size. Testicular atrophy and disturbances of spermiogenesis observed in male rats treated with terlipressin for 3 weeks could not be confirmed. Likewise no testicular effects were seen in any other repeat-dose toxicity study in rats and dogs.
No carcinogenicity studies have been performed with terlipressin.