V1 agonist · hepatorenal syndrome
A synthetic relative of vasopressin, the body's antidiuretic hormone, that narrows blood vessels. It is a hospital drug given intravenously to adults with hepatorenal syndrome, a rapid kidney failure that develops in advanced liver disease. Outside the US it has long been used for this condition and for bleeding esophageal varices.
Terlipressin is about twice as selective for vasopressin V1 receptors, which make blood vessels constrict, as for V2 receptors, which control how much water the kidney holds back. It acts in its own right and also as a prodrug that the body converts to lysine-vasopressin.
In cirrhosis, raised pressure in the portal vein and widened vessels in the gut draw blood away from the rest of the circulation, and the kidneys respond by reducing their own blood flow. By constricting those gut vessels, terlipressin lowers portal pressure, shifts blood back into the main circulation and raises mean arterial pressure, which is thought to restore kidney blood flow. It is given alongside albumin to expand blood volume. The same vessel-narrowing action explains its risk of reduced blood supply to the heart, gut and limbs.
The US approval rests on CONFIRM, a phase 3 trial in 300 adults with cirrhosis and type 1 hepatorenal syndrome who were randomized 2:1 to terlipressin or placebo, with albumin strongly recommended in both groups. Confirmed reversal of hepatorenal syndrome occurred in 32% on terlipressin versus 17% on placebo2. Survival was not better: by day 90, 51% of the terlipressin group and 45% of the placebo group had died, and deaths from respiratory causes were higher with terlipressin (11% vs 2%)2, the basis of the label's boxed warning1. For acute bleeding from esophageal varices, a 2003 Cochrane review pooling seven placebo-controlled trials with 443 patients found a 34% relative reduction in deaths with terlipressin3. That use is not FDA-approved.
FDA-approved in 2022 as Terlivaz (Mallinckrodt) to improve kidney function in adults with hepatorenal syndrome with a rapid reduction in kidney function. The label notes that patients with very high creatinine at the start are unlikely to benefit.
The FDA label carries a boxed warning for serious or fatal respiratory failure; patients with fluid overload or the most severe grade of acute-on-chronic liver failure are at higher risk, and oxygen levels must be checked before and throughout treatment. The most common effects are abdominal pain, nausea, respiratory failure, diarrhea and shortness of breath. Other warnings cover reduced blood supply to the heart, brain, gut or limbs, side effects that can make a patient ineligible for liver transplant, and harm to a fetus.
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