| Indication |
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. |
| Pharmacodynamics |
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. |
| Mechanism of action |
Prostaglandins are present in most body tissues and fluids and
mediate many biological functions. Epoprostenol (PGI2) is a member of
the family of prostaglandins that is derived from arachidonic acid. The
major pharmacological actions of epoprostenol is ultimately inhibition
of platelet aggregation. Prostacyclin (PGI2) is released by healthy
endothelial cells and performs its function through a paracrine
signaling cascade that involves G protein-coupled receptors on nearby
platelets and endothelial cells. The platelet Gs protein-coupled
receptor (prostacyclin receptor) is activated when it binds to PGI2.
This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP
goes on to inhibit any undue platelet activation (in order to promote
circulation) and also counteracts any increase in cytosolic calcium
levels which would result from thromboxane A2 (TXA2) binding (leading to
platelet activation and subsequent coagulation). PGI2 also binds to
endothelial prostacyclin receptors and in the same manner raise cAMP
levels in the cytosol. This cAMP then goes on to activate protein kinase
A (PKA). PKA then continues the cascade by phosphorylating and
inhibiting myosin light-chain kinase which leads to smooth muscle
relaxation and vasodilation. Notably, PGI2 and TXA2 work as
physiological antagonists. |
| Absorption |
Not Available |
| Volume of distribution |
|
| Protein binding |
Not Available |
| 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. |
| Route of elimination |
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. |
| Half life |
The in vitro half-life of epoprostenol in human blood at 37°C and
pH 7.4 is approximately 6 minutes; the in vivo half-life of epoprostenol
in humans is therefore expected to be no greater than 6 minutes. |
| Clearance |
Not Available |
| 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. |
