Epoprostenol

Epoprostenol

Names
Pronunciation	e" poe pros' ten nol
Trade names	Flolan, Veletri, others
Other names	Prostacyclin, prostaglandin I2 (PGI2)
IUPAC name (Z)-5-[(4R,5R)-5-Hydroxy-4-((S,E)-3-hydroxyoct-1-enyl)hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoic acid
Clinical data
Drug class	Prostaglandin
Main uses	Pulmonary arterial hypertension, ARDS
Side effects	Headache, dizziness, nausea, muscle pain, flushing, fast heart rate, low blood pressure
Pregnancy category	AU: B1 US: B (No risk in non-human studies)(Veletri); N (Flolan)
External links
AHFS/Drugs.com	Monograph
Legal
License data	US DailyMed: Epoprostenol_sodium
Legal status	AU: S4 (Prescription only) US: ℞-only
Pharmacokinetics
Elimination half-life	42 seconds
Chemical and physical data
Formula	C20H32O5
Molar mass	352.471 g·mol−1
3D model (JSmol)	Interactive image
SMILES OC(=O)CCC\C=C1\C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]2O1
InChI InChI=1S/C20H32O5/c1-2-3-4-7-14(21)10-11-16-17-12-15(8-5-6-9-20(23)24)25-19(17)13-18(16)22/h8,10-11,14,16-19,21-22H,2-7,9,12-13H2,1H3,(H,23,24)/b11-10+,15-8-/t14-,16+,17+,18+,19-/m0/s1 N Key:KAQKFAOMNZTLHT-OZUDYXHBSA-N N

Epoprostenol, also known as prostacyclin, is a medication and naturally occurring substance in the human body. As a medication it used to treat pulmonary arterial hypertension and acute respiratory distress syndrome (ARDS). It may also be used during dialysis when heparin cannot be used to prevent platelet aggregation. It may be given by continuous injection into a vein or inhaled.

Common side effects include headache, dizziness, nausea, muscle pain, flushing, fast heart rate, and low blood pressure. Other side effects may include bleeding. There is no evidence of harm in pregnancy, but such use has not been well studied. It is a prostaglandin and works by blocking platelet aggregation and dilating blood vessels.

Epoprostenol was approved for medical use in the United States in 1995. It is available as a generic medication. In the United Kingdom 1.5 mg costs the NHS about £45 as of 2021. In the United States this amount costs about 50 USD.

Medical uses

It is used to treat pulmonary arterial hypertension (PAH). Specifically, epoprostenol is given to people with class II or class IV PAH.

Side effects

Redness of the skin induced by intravenous epoprostenol

The side effects of this medication , prostacyclin, are the following (this is not an exhaustive list):

• Prolonged bleeding
• Rapid weight gain
• Redness of face, neck, arms, upper chest
• Blurred vision
• Chest congestion
• Chest pain
• Chills

Mechanism of action

Prostacyclin effect		Mechanism	Cellular response
Classical functions	Vessel tone	↑cAMP, ↓ET-1 ↓Ca2+, ↑K+	↓SMC proliferation ↑Vasodilation
	Antiproliferative	↑cAMP ↑PPARgamma	↓Fibroblast growth ↑Apoptosis
	Antithrombotic	↓Thromboxane-A2 ↓PDGF	↓Platelet aggregation ↓Platelet adherence to vessel wall
Novel functions	Antiinflammatory	↓IL-1, IL-6 ↑IL-10	↓Proinflammatory cytokines ↑Antiinflammatory cytokines
	Antimitogenic	↓VEGF ↓TGF-β	↓Angiogenesis ↑ECM remodeling

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 that 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, raises cAMP levels in the cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by promoting the phosphorylation of the myosin light chain kinase, which inhibits it and leads to smooth muscle relaxation and vasodilation. It can be noted that PGI₂ and TXA₂ work as physiological antagonists.

Function

Prostacyclin (PGI₂) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). It does this by inhibiting platelet activation. It is also an effective vasodilator. Prostacyclin's interactions contrast with those of thromboxane (TXA₂), another eicosanoid. These strongly suggest a mechanism of cardiovascular homeostasis between these two hormones in relation to vascular damage.

Degradation

Prostacyclin, which has a half-life of 42 seconds, is broken down into 6-keto-PGF₁, which is a much weaker vasodilator.

Pharmacology

Ball-and-stick model of prostacyclin

Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:

• as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb;
• in pulmonary hypertension.
• in primary pulmonary hypertension (PPH)

The production of prostacyclin is inhibited by the action of NSAIDs on cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to prostaglandin H2 (PGH₂), the immediate precursor of prostacyclin. Since thromboxane (an eicosanoid stimulator of platelet aggregation) is also downstream of COX enzymes, one might think that the effect of NSAIDs would act to balance. However, prostacyclin concentrations recover much faster than thromboxane levels, so aspirin administration initially has little to no effect but eventually prevents platelet aggregation (the effect of prostaglandins predominates as they are regenerated). This is explained by understanding the cells that produce each molecule, TXA₂ and PGI₂. Since PGI₂ is primarily produced in a nucleated endothelial cell, the COX inhibition by NSAID can be overcome with time by increased COX gene activation and subsequent production of more COX enzymes to catalyze the formation of PGI₂. In contrast, TXA₂ is released primarily by anucleated platelets, which are unable to respond to NSAID COX inhibition with additional transcription of the COX gene because they lack DNA material necessary to perform such a task. This allows NSAIDs to result in PGI₂ dominance that promotes circulation and retards thrombosis.

In patients with pulmonary hypertension, inhaled epoprostenol reduces pulmonary pressure, and improves right ventricular stroke volume in patients undergoing cardiac surgery. A dose of 60 μg is hemodynamically safe, and its effect is completely reversed after 25 minutes. No evidence of platelet dysfunction or an increase in surgical bleeding after administration of inhaled epoprostenol has been found. The drug has been known to cause flushing, headaches and hypotension.

Synthesis

Biosynthesis

Eicosanoid synthesis. (Prostacyclin near bottom center.)

Prostacyclin is produced in endothelial cells, which line the walls of arteries and veins, from prostaglandin H₂ (PGH₂) by the action of the enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it is called PGI₂ (prostaglandin I₂) in eicosanoid nomenclature, and is a member of the prostanoids (together with the prostaglandins and thromboxane). PGI2, derived primarily from COX-2 in humans, is the major arachidonate metabolite released from the vascular endothelium. This is a controversial point, some assign COX 1 as the major prostacyclin producing cyclooxygenase in the endothelial cells of the blood vessels.

The series-3 prostaglandin PGH₃ also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI₃. The unqualified term 'prostacyclin' usually refers to PGI₂. PGI₂ is derived from the ω-6 arachidonic acid. PGI₃ is derived from the ω-3 EPA.

Artificial synthesis

Prostacyclin can be synthesized from the methyl ester of prostaglandin F_2α. After its synthesis, the drug is reconstituted in saline and glycerin.

History

During the 1960s, a UK research team, headed by Professor John Vane, began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Vane discovered that aspirin and other oral anti-inflammatory drugs work by inhibiting the synthesis of prostaglandins. This critical finding opened the door to a broader understanding of the role of prostaglandins in the body.

A team at The Wellcome Foundation led by Salvador Moncada had identified a lipid mediator they called "PG-X," which inhibits platelet aggregation. PG-X, later known as prostacyclin, is 30 times more potent than any other then-known anti-aggregatory agent.

In 1976, Vane and fellow researchers Salvador Moncada, Ryszard Gryglewski, and Stuart Bunting published the first paper on prostacyclin in Nature. The collaboration produced a synthesized molecule, which was named epoprostenol. But, as with native prostacyclin, the epoprostenol molecule is unstable in solution and prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications.

To overcome this challenge, the research team that discovered prostacyclin continued the research. The research team synthesized nearly 1,000 analogues.

Society and culture

Brands

Brands
Flolan (epoprostenol) for Injection	Continuously infused	2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved	Class III Class IV
Veletri (epoprostenol) for Injection	Continuously infused	2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved	Class III Class IV
Remodulin SC§ (treprostinil sodium) Injection	Continuously infused	1.25 ng/kg/min to start, increased by up to 1.25 ng/kg/min per week for 4 weeks, then up to 2.5 ng/kg/min per week until suitable efficacy/tolerability balance is achieved	Class II Class III Class IV
Ventavis (iloprost) Inhalation Solution	Inhaled 6–9 times daily	2.5 μg 6–9 times daily to start, increased to 5.0 μg 6–9 times daily if well tolerated	Class III Class IV

External links

Identifiers:	ATC code: B01AC09 (WHO) CAS Number: 35121-78-9 Y PubChem CID: 5282411 IUPHAR/BPS: 1915 DrugBank: DB01240 N ChemSpider: 102770 N UNII: DCR9Z582X0 KEGG: D00106 D01337 ChEMBL: ChEMBL1139 N

• "Epoprostenol". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-04-27. Retrieved 2021-10-24.
• "Epoprostenol sodium". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-06-25. Retrieved 2021-10-24.