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DOI: 10.1055/s-2002-35557
Sildenafil zur Therapie der schweren pulmonalen Hypertonie und des beginnenden Rechtsherzversagens
Sildenafil for Treatment of Severe Pulmonary Hypertension and Commencing Right-Heart Failure Anlässlich der Emeritierung und zu Ehren von Herrn Professor Dr. med. Helmut Fabel, Pneumologie, Medizinische Hochschule Hannover.Publikationsverlauf
Publikationsdatum:
20. November 2002 (online)
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Zusammenfassung
Pathophysiologisch liegen der pulmonalen Hypertonie (PHT) im Wesentlichen vier Veränderungen des Lungengefäßsystems zugrunde: 1. Vasokonstriktion, 2. Gefäßrarefizierung, 3. reduzierte Gefäßelastizität und 4. Obliteration des Gefäßlumens (thrombotisches Material) mit sekundärem zellulären Umbau der Gefäßwände (vaskuläres Remodelling). Konsequenz der resultierenden Druck- und Widerstandserhöhung ist die Überlastung des rechten Ventrikels (chronisches Rechtsherzversagen). Ziel der neueren Interventionsstrategien ist erstens: die Aufhebung des dauerhaft erhöhten Vasotonus durch Relaxation der glatten Gefäßmuskulatur (Vasorelaxanzien), zweitens: eine langfristige Antagonisierung des strukturellen Gefäßumbaus (vaskuläres Remodelling) und drittens: die Verhinderung einer primär oder sekundär eintretenden thrombotisch bedingten Obliteration (Embolie, in situ Thrombose). Bisher werden vornehmlich hochdosierte Kalziumantagonisten (jedoch nur in 10 - 15 % der Fälle anwendbar), vasodilatative Prostanoide (z. B. Prostazyklin, Iloprost) sowie der kürzlich für die Behandlung der pulmonalarteriellen Hypertonie zugelassene unselektive Endothelinantagonist Bosentan therapeutisch eingesetzt. Die Anwendbarkeit ist durch die zum Teil gravierenden Nebenwirkungen und/oder aufwändigen parenteralen Applikationsformen eingeschränkt. Neuere Daten weisen auf eine starke, pulmonal vasodilatative Potenz des selektiven Phosphodiesterase-5 (PDE-5) Inhibitors Sildenafil hin. Klinische Studien mit kleinen Fallzahlen sowie zahlreiche Einzelfallberichte unterstreichen die gute Verträglichkeit dieser oral applizierbaren Substanz bei verschiedenen Formen der PHT. Aufgrund der bisherigen ermutigenden Ergebnisse, der einfachen Verfügbarkeit des Medikamentes und des im Verhältnis zu den etablierten Therapien günstigen Preises wird Sildenafil bereits zur Therapie der PHT im so genannten „off-label use” verwendet. Vor einer generellen Empfehlung sollten die Wirksamkeit und Sicherheit dieses neuen Therapieansatzes jedoch durch kontrollierte Studien bestätigt werden.
Abstract
Pulmonary hypertension (PHT) is mainly explained by four underlying pathophysiological phenomena: 1. Vasoconstriction, 2. reduction of pulmonary vascular bed, 3. reduction in vessel elasticity, and 4. obliteration of the vessel lumen by thrombotic material and subsequent cellular alterations of the vessel wall (vascular remodeling). Chronic right heart load is thus a consequence of increased pulmonary pressure and vascular resistance. Main targets of advanced therapeutic strategies are therefore first: resolution of chronically increased vascular tone by smooth muscle cell relaxation (vasodilators), second: reversal of vascular remodeling and third: prevention from pulmonary embolization and/or in-situ thrombosis (chronic anticoagulation). Long term administration of high dose calcium channel blockers (though operative only in a minority of 10 - 15 % of all patients), prostanoids (eg. prostacyclin, iloprost), and the recently approved unselective oral endothelin antagonist bosentan are regarded as established medical therapies for treatment of chronic PHT. However, applicability of these substances can be limited by potentially serious adverse events and/or necessity for elaborate parenteral application. Recent data are indicative for a strong pulmonary vasodilative potency of the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil. Smaller clinical studies and numerous case reports underline the good tolerability of this orally applied substance in various form of PHT. Based on these encouraging results, the simple availability, and the low costs (in comparison to “established therapies”) of the drug, sildenafil is currently widely used in an “off-label” indication for treatment of PHT. Controlled randomized studies have to confirm the current findings, before general recommendations regarding the use of sildenafil for treatment of PHT can be made.
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Prof. Dr. Dr. F. Grimminger
Medizinische Klinik II
Klinikstr. 36
35392 Gießen
eMail: friedrich.grimminger@innere.med.uni-giessen.de