Pharmakologie der Heparine und der direkten Antikoagulanzien

Zusammenfassung

Jahrzehntelang beschränkten sich die Optionen für die Anti koagulation auf unfraktioniertes Heparin (UFH) und Vitamin-K-Antagonististen (VKA). Mit der Einführung der niedermolekularen Heparine (NMH) wurde die kurz- und mittelfristige Antikoagulation entscheidend verbessert; eine Alternative zu den VKA für die Langzeitanwendung steht noch aus. Da die Heparine belegen, dass Faktor Xa und Thrombin geeignete Angriffspunkte für die Antikoagulation darstellen, konzentriert sich die industrielle Antikoagulanzien- Forschung auf die Entwicklung direkter Thrombin- (DTI) und Faktor-Xa-Inhibitoren (DXI). Die verfügbaren bzw. in der Entwicklung am weitesten fortgeschrittenen Antikoagulanzien lassen sich in zwei Klassen einteilen: 1.) Glyko-Antikoagulanzien mit den natürlichen sulfatierten Glykosaminoglykanen (GAG) (UFH, NMH, Danaparoid) und den synthetisch hergestellten Oligosacchariden (Fondaparinux, Idraparinux und SR123781A), 2.) Xenobiotika, d. h. Proteine und chemisch-synthetische Moleküle. Die Glyko-Antikoagulanzien wirken partiell (GAG) oder ausschließlich (Oligosaccharide) durch die Katalyse von Antithrombin (AT), während die Xenobiotika direkt Thrombin oder Faktor Xa hemmen. Zurzeit stehen mit Lepirudin, Bivalirudin, Argatroban drei parenterale DTI sowie mit Dabigatranetelxilat ein oraler DTI für begrenzte Anwendungsgebiete zur Verfügung. Mit Rivaroxaban wurde kürzlich der erste orale DXI zugelassen. In dieser Übersicht werden die Entwicklung der Antikoagulanzien und das pharmakologische Profil der in der Praxis eingesetzten Antikoagulanzien beschrieben.

Summary

For decades, the options for therapeutic anticoagulation were limited to unfractionated heparin (UFH) and vitamin K antagonists (VKA), and their well-known limitations had to be accepted. With the introduction of the various LMWHs, the short- and medium-term anticoagulation could be much improved, but an alternative to VKA is still missing The heparins provided the proof of concept that FXa and thrombin represent suitable targets for therapeutic anticoagulation. Consequently, the search for new anticoagulants focuses on inhibitors of thrombin (DTI) or FXa (DXI). Apart from the VKA, the anticoagulants presently available or in an advanced stage of development can thus be divided in two classes: One are the glyco-anticoagulants with the natural sulfated glycosaminoglycans (GAGs) (UFH, LMWHs, and danaparoid) and the synthetic oligosaccharides (OS) (fondaparinux, idraparinux, and SR123781A). The other class are the xenobiotic anticoagulants, i.e. proteins and synthetic chemical entities. Die glyco-anticoagulants act partially (GAGs) or exclusively (oligosaccharides) by catalysing antithrombin, whereas the xenobiotic anticoagulants are direct inhibitors of either thrombin or FXa. At present, three parenteral DTI (lepirudin, argatroban, and bivalirudin) and since March 2008 one oral DTI (dabigatran etexilate) are clinically used for limited indications. In September 2008 rivaroxaban has been approved as the first oral DXI. This review describes the development of the anticoagualants as well as the pharmacological profile of the clinically used anticoagualants.

Schlüsselwörter

Glykosaminoglykane - niedermolekulare Heparine - Danaparoid - Fondaparinux - Idraparinux - SR123781A - direkte Thrombininhibitoren - direkte Faktor-Xa-Inhibitoren - Lepirudin - Bivalirudin - Argatroban - Ximelagatran - Dabigatranetexilat - Rivaroxaban

Keywords

Glycosaminoglycans - low molecular weight heparins - fondaparinux - idraparinux - SR123781A - direct thrombin inhibitors - direct factor Xa inhibitors - lepirudin - bivalirduin - argatroban - ximelagatran - dabigatran etexilate - rivaroxaban

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