title: Phosphodiesterase type 5 inhibitors in pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and tadalafil plasma levels. Due to their clinical effectiveness, tolerance profile, and their oral administration, sildenafil and tadalafil are two of the recommended first-line therapies for PAH patients in World Health Organization functional classes II or III.
authors.affiliation: Université Paris-Sud, Orsay, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.forename: Marie-Camille
authors.initials: MC
authors.lastname: Chaumais
authors.forename: Laurent
authors.initials: L
authors.lastname: Savale
authors.forename: Delphine
authors.initials: D
authors.lastname: Natali
authors.forename: Laura C
authors.initials: LC
authors.lastname: Price
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
mesh_terms: D000465:Algorithms; D002243:Carbolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011668:Pulmonary Veno-Occlusive Disease / Q000150:complications; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000068581:Tadalafil; D014227:Triazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000069058:Vardenafil Dihydrochloride
chemical_list: D002243:Carbolines; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate