Prostacyclin

Overview

Prostacyclin (also called prostaglandin I₂ or PGI₂) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. WP

When used as a drug, it is also known as epoprostenol. The terms are sometimes used interchangeably.[1][2] WP

Uses, dosage and effects

Medical uses

It is used to treat pulmonary arterial hypertension (PAH), pulmonary fibrosis, as well as atherosclerosis. In pediatric practice, prostacyclin is commonly used to mantain patency of the ductus arteriosus. Prostacyclins are given to people with class III or class IV PAH.[3–7] WP

Pharmacology

Mechanism

As mentioned above, 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. WP

Pharmacology

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

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

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. WP

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.[8][9] WP

History

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. WP

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. They did this while searching for an enzyme that generates a fellow unstable prostanoid, Thromboxane A2[10] WP

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.[11] WP⚠ Wikipedia itself has flagged this text: citation needed.

To overcome this challenge, the research team that discovered prostacyclin continued the research. The research team synthesized nearly 1,000 analogues. WP⚠ Wikipedia itself has flagged this text: citation needed.

Chemistry

Formula

C20H32O5 PC

CAS number

35121-78-9 PC

Molar mass (g/mol)

352.5 PC

IUPAC name (computed by PubChem)

(5Z)-5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxyoct-1-enyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-ylidene]pentanoic acid PC

SMILES

CCCCC[C@@H](/C=C/[C@H]1[C@@H](C[C@H]2[C@@H]1C/C(=C/CCCC(=O)O)/O2)O)O PC

InChIKey

KAQKFAOMNZTLHT-OZUDYXHBSA-N PC

PubChem CID

5282411

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other DorlandsDict three/000036426 epoprostenol
2. Journal / agency Kermode J, Butt W, Shann F. Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery. British Heart Journal. August 1991. doi:10.1136/hrt.66.2.175 · PMID 1883670 · PMC1024613
3. Journal / agency Ruopp NF, Cockrill BA. Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review. JAMA. April 2022. doi:10.1001/jama.2022.4402 · PMID 35412560
4. Other Epoprostenol Sodium Monograph for Professionals. 6 April 2020
5. Journal / agency Flolan- epoprostenol sodium injection, powder, lyophilized, for solution Diluent- water solution. 15 November 2019
6. Journal / agency Stitham J, Midgett C, Martin KA, Hwa J. Prostacyclin: an inflammatory paradox. Frontiers in Pharmacology. 13 May 2011. doi:10.3389/fphar.2011.00024 · PMID 21687516 · PMC3108482
7. Journal / agency Hassoun PM. Pulmonary Arterial Hypertension. The New England Journal of Medicine. December 2021. doi:10.1056/NEJMra2000348 · PMID 34910865
8. Journal / agency Haché M, Denault A, Bélisle S, Robitaille D, Couture P, Sheridan P, Pellerin M, Babin D, Noël N, Guertin MC, Martineau R, Dupuis J. Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery. The Journal of Thoracic and Cardiovascular Surgery. March 2003. doi:10.1067/mtc.2003.107 · PMID 12658208
9. Other Nickson, C. (2015, October 28). Prostacyclin or Epoprostenol. Retrieved November 16, 2015, from
10. Journal / agency Bunting S, Gryglewski R, Moncada S,Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac ateries and inhibits platelet aggregation. Prostaglandins. 1976. doi:10.1016/0090-6980(76)90125-8 · PMID 1005741
11. Journal / agency Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. October 1976. doi:10.1038/263663a0 · PMID 802670

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.