Epoprostenol

Toxicity

Symptoms of overdose are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of epoprostenol. Single intravenous doses at 10 and 50 mg/kg (2703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia.

Originator

Prostacyclin,ZYF Pharm Chemical

The Uses of Epoprostenol

Inhibitor (platelet). [Names previously used: Prostacyclin, PGI2, Prostagland in I2, Prostaglandin X, PGX].

Background

A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension.

Indications

For the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.

Definition

ChEBI: Prostaglandin I2 is a prostaglandins I. It has a role as a mouse metabolite. It is a conjugate acid of a prostaglandin I2(1-).

Manufacturing Process

Preparation of prostacyclin:
Pig aortas were stripped of adventitia, snap frozen in liquid nitrogen, crushed into a fine powder, resuspended in 0.05 M Tris buffer (pH 7.5) (1:4, w:v) andhomogenised at high speed in a Polytron (KIMENATIC, LUCERNE, SWITZERLAND) homogenizer. The homogenate was centrifuged for 15 min and the resulting supernatant centrifuged again for 5 min. The pellet was discarded, while the pellet obtained after centrifugation of the supernatant was resuspended in deionized water and lyophilized. An average yield of 150 mg of aortic microsomal powder (51% protein) per 100 g of aortic tissue was obtained.

brand name

Flolan (GlaxoSmithKline).

Therapeutic Function

Platelet aggregation inhibitor, Antimetastatic

Pharmacokinetics

Epoprostenol has two major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated brudycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol.

Metabolism

Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans.