Epoprostenol

Epoprostenol Sodium, the monosodium salt of epoprostenol, a naturally occurring prostaglandin produced by the intima of blood vessels. Epoprostenol is the most potent inhibitor of platelet aggregation known. It is also a potent vasodilator.

Many of the actions of epoprostenol are exerted via the stimulation of adenylate cyclase, which leads to increased intracellular levels of cyclic adenosine 3’5' monophosphate (cAMP). A sequential stimulation of adenylate cyclase, followed by activation of phosphodiesterase, has been described in human platelets. Elevated cAMP levels regulate intracellular calcium concentrations by stimulating calcium removal, and thus platelet aggregation is ultimately inhibited by the reduction of cytoplasmic calcium, upon which platelet shape change, aggregation and the release reaction depends.

Pharmacodynamic effects

An infusion of 4 ng/kg/min for 30 minutes has been shown to have no significant effect on heart rate or blood pressure, although facial flushing may occur at this level.

Pulmonary Arterial Hypertension

Intravenous epoprostenol infusions of up to 15 minutes have been found to produce dose-related increases in cardiac index (CI) and stroke volume (SV), and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR) and mean systemic arterial pressure (SAPm). The effects of epoprostenol on mean pulmonary artery pressure (PAPm) in patients with idiopathic or heritable PAH were variable and minor.

Renal Dialysis

The effects of epoprostenol on platelet aggregation is dose-related when between 2 and 16 ng/kg/min is administered intravenously, and significant inhibition of aggregation induced by adenosine diphosphate is observed at doses of 4 ng/kg/min and above.

Effects on platelets have been found to disappear within 2 hours of discontinuing the infusion, and haemodynamic changes due to epoprostenol to return to baseline within 10 minutes of termination of 60 minutes infusion at 1 to 16 ng/kg/min.

Higher circulating doses of epoprostenol (20 ng/kg/min) disperse circulating platelet aggregates and increase by up to two-fold the cutaneous bleeding time.

Epoprostenol potentiates the anticoagulant activity of heparin by approximately 50%, possibly reducing the release of heparin neutralising factor.

Due to the chemical instability, high potency and short half-life of epoprostenol, no precise and accurate assay has been identified as appropriate for quantifying epoprostenol in biological fluids.

Intravenously administered epoprostenol is rapidly distributed from blood to tissue.

At normal physiological pH and temperature, epoprostenol breaks down spontaneously to 6-oxo-prostaglandin F1 alpha, although there is some enzymatic degradation to other products.

Following the administration of radiolabelled epoprostenol to humans, at least 16 metabolites were found, 10 of which were structurally identified.

Unlike many other prostaglandins, epoprostenol is not metabolised during passage through the pulmonary circulation.

The half-life for the spontaneous breakdown to 6-oxo-prostaglandin F1 alpha in man is expected to be no more than 6 minutes, and may be as short as 2 to 3 minutes, as estimated from in vitro rates of degradation of epoprostenol in human whole blood.

Following the administration of radiolabelled epoprostenol to humans, the urinary and faecal recoveries of radioactivity were 82% and 4%, respectively.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. No long-term animal studies have been conducted to determine the carcinogenic potential of epoprostenol.