Terlipressin

Terlipressin has low pharmacological activity but is converted to the active lysine vasopressin by enzyme cleavage.

Doses of 0.85 mg terlipressin (corresponding to 1 mg terlipressin acetate) and 1.7 mg terlipressin (corresponding to 2 mg terlipressin acetate) reduce portal vein pressure and cause a noticeable vasoconstriction. Lowering the portal pressure and reducing the blood flow of the azygos vein is dose dependent. The effect of the low dose wears off after 3 hours, while hemodynamic data show that 1.7 mg terlipressin is more effective than 0.85 mg, since the higher dose shows a more reliable effect over the entire treatment period (4 hours).

Terlipressin inhibits portal hypertension with simultaneous reduction of blood circulation in portal vessels. Terlipressin contracts smooth oesophageal muscle with consecutive compression of oesophageal varices.

The inactive pre-hormone terlipressin slowly releases bioactive lysine-vasopressin. Metabolic elimination takes place concomitantly and within a period of 4-6 hours. Therefore, concentrations remain continuously above the minimal effective dose and below toxic concentrations.

Specific effects of terlipressin are assessed as follows:

Gastrointestinal system: Terlipressin increases the tone of vascular and extravascular smooth muscle cells. The increase in arterial vascular resistance leads to decrease of splanchnic hypervolemia. The decrease of the arterial blood supply leads to reduction of pressure in the portal circulation. Intestinal muscles contract concomitantly which increases intestinal motility. The muscular wall of the oesophagus also contracts which leads to closure of experimentally induced varice.

Kidneys: Terlipressin has only 3% antidiuretic effect of the native vasopressin. This residual activity is of no clinical significance. Renal blood circulation is not significantly affected in normovolemic condition. Renal blood circulation is increased, however, under hypovolemic condition.

Blood pressure: Terlipressin induces a slow haemodynamic effect which lasts 2-4 hours. Systolic and diastolic blood pressure increase mildly. More intense blood pressure increase has been observed in patients with renal hypertension and general blood vessel sclerosis.

Heart: All studies reported that no cardio-toxic effects were observed, not even under the highest dose of terlipressin. Influences on the heart, such as bradycardia, arrhythmia, coronary insufficiency, occur possibly because of reflex or direct vascular constrictive effects of terlipressin.

Uterus: Terlipressin causes significant decrease in myometrial and endometric blood flow.

Skin: The vasoconstrictive effect of terlipressin causes significant decrease in blood circulation of the skin. All studies reported obvious paleness on face and body.

In conclusion, the main pharmacological properties of terlipressin are its haemodynamic effects and its effects on smooth muscle. The centralization effect under hypovolemic condition is a desired side effect in patients with bleeding oesophageal varices.

The mean plasma half-life of terlipressin is 24 minutes. After bolus intravenous injection terlipressin elimination follows second order kinetics. Plasma half-life was calculated as 8-12 minutes during the distribution phase (0-40 minutes) and 50-80 minutes during the elimination phase (40-180 minutes). The release of lysine-vasopressin is maintained for at least 180 minutes. Due to cleavage of the glycyl groups from terlipressin lysine-vasopressin is slowly released and reaches maximal concentrations after 120 minutes. Urine contains only 1% of the injected terlipressin, which indicates almost complete metabolism by endo- and exopeptidases of liver and kidneys.

Non-clinical data reveal no special hazard for humans based on conventional studies of single- and repeat-dose toxicity, and genotoxicity. No carcinogenicity studies have been performed with terlipressin.

At doses relevant to humans, the only effects observed in animals were those attributed to the pharmacological activity of terlipressin.

Animal pharmacokinetic data are not available to compare with the plasma concentrations in humans at which these effects have occurred, however, since administration is intravenous, substantial systemic exposure can be assumed.

Due to its pharmacological effect on smooth muscles terlipressin may induce abortion in the first trimester.

An embryo-fetal study in rats demonstrated no adverse effects of terlipressin. 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.