Prostacyclin

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Structural formula
Structure of prostacyclin
General
Non-proprietary name Epoprostenol
other names
  • ( Z ) -5 - [(3a R , 4 R , 5 R , 6a S ) -5-hydroxy-4 - [( E , 3 S ) -3-hydroxyoct-1-enyl] hexahydro-2 H -cyclopenta [ b ] furan-2-ylidene] pentanoic acid
  • (5 Z , 9 α , 11 α , 13 E , 15 S ) -6,9-epoxy-11,15-dihydroxy-prosta-5,13-diene-1-acid
Molecular formula C 20 H 32 O 5
External identifiers / databases
CAS number 35121-78-9
PubChem 5282411
DrugBank DB01240
Wikidata Q412050
Drug information
ATC code

B01 AC09

Drug class

Prostaglandins

properties
Molar mass 352.47 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Prostacyclin (or synonym prostaglandin I 2 , PGI 2 for short ) is an eicosanoid and belongs to the group of series 2 prostaglandins , these are the pro-inflammatory prostaglandins from arachidonic acid .

history

Interest in the use of prostaglandins as vasodilators was aroused early on after their discovery. Alprostadil (PGE 1) was first used in 1973 with good results for arteriosclerotic vascular diseases. Six years later, prostacyclin was first used successfully in therapy for peripheral arterial disease. The major disadvantage of these substances, however, was their significant instability. For this reason, research was carried out on derivatives that are more stable. As a result, the synthetic iloprost was developed, which had a significantly higher metabolic stability. It was launched on the German market in 1993 as Ilomedin .

education

Prostacyclin is formed in endothelial cells with the aid of prostacyclin synthase from prostaglandin PGH 2 from arachidonic acid . Arachidonic acid is a semi-essential omega-6 fatty acid and is found in numerous foods. Their proportion is particularly high in pork lard (1700 mg per 100 g), pork liver (870 mg per 100 g), egg yolk (297 mg per 100 g), tuna (280 mg per 100 g) and liver sausage (230 mg per 100 g) .

Effects

Prostacyclin binds to the IP receptor , a G-protein-coupled membrane receptor , and has various effects through it:

inflammation

PGI 2 , together with PGE 2, is the main prostaglandin involved in the inflammatory process. It increases vascular permeability (which causes tissue swelling), is involved in the development of redness (which is caused by increased blood flow) and intensifies pain (which is caused by other inflammatory substances such as bradykinin or histamine ) by sensitizing nociceptive nerve endings ( by lowering the activation threshold for tetrodotoxin-resistant sodium channels on sensitive nerves). IP receptors increase in sensory neuron activity of adenylyl cyclase and the phospholipase A and so modulate the activity of ion channels and neurotransmitter release by the activation of protein kinase A and protein kinase C .

Cardiovascular system

Prostacyclin has a strong vasodilator effect and inhibits platelet aggregation.

  1. Vascular cells form many prostaglandins , but prostacyclin is the main prostaglandin , which is formed by the endothelial cells of the vessels in which the prostaglandin-I synthase is concentrated. Prostacyclin binds to the G-protein-coupled prostacyclin receptor of the smooth muscle cells of the vessels and inhibits vascular contraction by increasing the intracellular cAMP . It is an opponent of the thromboxane, which is mostly formed in platelets .
  2. It also inhibits the MAP kinase pathway .
  3. It inhibits platelet aggregation and is therefore a functionally antagonist of the thromboxane, which is mainly formed in the platelets.

Prostacyclin causes reperfusion or improvement and suppression of the blood circulation.

Endogenous prostacyclin is mainly formed in the vascular endothelium and smooth muscles. It has a vasodilatory, antiproliferative and cytoprotective effect. Prostacyclin is the most potent endogenous platelet aggregation inhibitor (TAH).

The platelet aggregation inhibition comes about through an inhibitory effect on platelets. Prostacyclin is eliminated to 70% renally and is mainly metabolised by the liver.

lung

Here, too, it mainly expands the pulmonary vessels and prevents microthrombi. It is also a weak bronchodilator . The prostacyclin blood levels of patients increase under general anesthesia and ventilation to 15-20 times the norm.

pharmacology

Therapeutic use

Prostacyclin (epoprostenol) and prostacyclin analogues (iloprost, treprostinil ) are used therapeutically to treat Raynaud's syndrome , pulmonary hypertension , and in off-label use also bone marrow edema and femoral head necrosis .

The synthetic analog iloprost is also used therapeutically.

In patients with heparin-induced thrombocytopenia (HIT) , prostacyclin can be used in off-label use , if e.g. B. for a heart operation with a heart-lung machine heparin must be given. Prostacyclin as a continuous infusion protects the platelets from activation and clumping as long as heparin is present in the bloodstream.

The synthetic iloprost is a stable analogue of the body's own prostacyclin. It is approved for the treatment of acute ischemic events due to peripheral arteriosclerotic occlusions or diabetic angiopathies , as well as for the treatment of pulmonary hypertension . It is also used in the therapy of scleroderma and Raynaud's syndrome .

Contraindications

Exclusion criteria for treatment are pregnancy, treatment with warfarin or heparin, heart defects, previous myocardial infarction or unstable angina pectoris. In the case of regional anesthesia procedures close to the spinal cord ( spinal anesthesia or epidural anesthesia ), prostacyclin should be discontinued 30 minutes beforehand, but can be given again immediately after the procedure.

Interactions

Known side effects with the active ingredient prostacyclin are, in particular because of the initially occurring vasodilatory hypotension, headache, flush (facial redness), sweating and nausea, also cardiac side effects such as angina pectoris symptoms up to EKG changes. Agitation, diarrhea, fever, paresthesia, myalgia, arrhythmia, extrasystoles, pulmonary embolism and kidney pain can also occur. According to, side effects such as bleeding such as B. epistaxis (nosebleeds) or haemoptysis (bloody sputum from the airways), especially if other blood-thinning drugs (anticoagulants) are also taken. The risk of bleeding may be increased in patients who are also being treated with other anti-platelet agents or anticoagulants (agents that stop the blood from clotting).

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Arachidonic Acid Metabolism  - Learning and Teaching Materials

Individual evidence

  1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  2. ↑ a b External identifiers of or database links to Iloprost : CAS number: 73873-87-7, PubChem : 5311181 , ChemSpider : 25995410 , DrugBank : DB01088 , Wikidata : Q2718713 . Other names: ( E ) -5 - {(3a S , 4 R , 5 R , 6a S ) -5-hydroxy-4 - [( E ) - (3 S , 4 RS ) -3-hydroxy-4-methyloct -1-en-6-ynyl] perhydropentalen-2-ylidene} pentanoic acid; Ciloprost; ZK 36374 (Schering). Molecular formula: C 22 H 32 O 4 . Molar mass: 360.49 g / mol.
  3. ^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 165 .
  4. ↑ Simmons D et al. Cyclooxygenase Isoenzymes: The Biology of Prostaglandin Synthesis and Inhibition. Pharmacol Rev 2004; 56: 387-437.
  5. ↑ Thorsten Schmidt: Infusion, femoral head drilling or infusion after femoral head drilling in the treatment of atraumatic femoral head necrosis (FKN) and bone marrow edema syndrome , dissertation, University of Regensburg 2009, p. 19 (PDF; 1.3 MB).
  6. ↑ Petje et al. Aseptic bone necrosis in childhood. Orthopedist 10 (2002) 1027-1038. doi : 10.1007 / s00132-004-0634-3
  7. ↑ Heparin-induced thrombocytopenia and cardiac surgery. Retrieved December 16, 2018 .
  8. ↑ Wiebke Gogarten, Hugo Van Aken: Perioperative thrombosis prophylaxis - platelet aggregation inhibitors - importance for anesthesia In: AINS - anesthesiology · intensive care medicine · emergency medicine · pain therapy. 47, 2012, pp. 242-252, doi : 10.1055 / s-0032-1310414 .
  9. ↑ SA Kozek-Langenecker, D. Fries, M. Gütl, N. Hofmann, P. Innerhofer, W. Kneifl, L. Neuner, P. Perger, T. Pernerstorfer, G. Pfanner, et al .: Locoregional anesthesia under anticoagulant medication. Recommendations of the Perioperative Coagulation Working Group (AGPG) of the Austrian Society for Anaesthesiology and Intensive Care Medicine (ÖGARI). THE ANESTHESIST Volume 54, Number 5 (2005), 476-484, doi : 10.1007 / s00101-005-0827-0 .
  10. ↑ Ventavis (Bayer Schering) with active ingredient: iloprost , effects and side effects.