Group II pulmonary hypertension due to left heart disease (PH-LHD) is the most common among pulmonary hypertension patients worldwide. Particularly, the valvular heart disease (VHD) is the leading causes of this type of PH. Mitral and aortic valve diseases increase the progress of PH and activate a cascade of venous and small artery remodeling, nonreversible arterial pulmonary hypertension, and right ventricular dysfunction. The research on therapy for PH–LHD during the last decade was vast. Most of the drug candidate was focused on pulmonary vasodilation, endothelial function, and vascular remodeling. 5-phosphodiesterase (PDE5) inhibitors drug has effectiveness in treating pulmonary arterial hypertension, but the outcome is insignificant in the field. Sildenafil and other PDE5 inhibitors are often used off-label to alleviate this condition. It has developed as a potent first-line oral therapeutic drug candidate for symptomatic PAH patients who do not have indications for treatment with intravenous prostacyclin.
How Effective is Sildenafil for Group 2 Pulmonary Hypertension?
Sildenafil compound was developed in the year 1986 by Pfizer group to treat hypertension. The trial compound is selective and had shown the potent antagonistic activity to PDF-5 (phosphodiesterase type 5), causing vasodilation and platelet inhibition. This turns out to be an effective alternative to other drugs drug for angina for the treatment of PH. It is generally prescribed as an oral drug with no other drug interactions. It is a well-tolerated drug, doesn’t require continuous monitoring. Sildenafil found in high concentrations in pulmonary arteries and the corpora cavernosum and significantly involved in antiproliferative effects. It has not been associated with major adverse effects in any of the subtypes of PH, for which it has been studied.
Sildenafil prevents the breakdown of cGMP and increases its level indirectly. cGMP cause vasodilation, which in turn decrease the pressure, which predominantly occurs from the modulation of ion channel activity by cGMP. Vasodilators (sildenafil) increase the blood flow (improves hemodynamics) and also prevents remodeling via NO and cGMP modulation of smooth muscle proliferation and apoptosis. One of the research studies has shown that sildenafil obstructed platelet-derived growth factor (PDGF)-induced DNA synthesis and cell proliferation, and inhibited hypoxia-induced cell proliferation. Breakdown of sildenafil happens mostly by the enzyme hepatic cytochrome P450. Elder patients with creatinine clearance less than 30 and with hepatic cirrhosis have reduced clearance of sildenafil. During exercise testing, peak oxygen consumption was higher in the sildenafil-treated group than the placebo group.
There is a small case of the report available on safety and efficacy of sildenafil. But, the use of this drug amongst pulmonary hypertension patients has increased intensely. Future large, well-designed trials are critical to direct physicians in the treatment of unstudied populations who might benefit from sildenafil.
Treprostinil (subcutaneous) with sildenafil (oral) combination has improved the condition of chronic PH patients. Exercise treadmill time and dyspnea fatigue score were better and response among patients was positive. Another study patients with idiopathic PAH, CREST (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), congenital vascular defect, and chronic thromboembolic disease treated with inhaled nitric oxide (NO) followed by inhaled iloprost plus sildenafil. With combined iloprost and sildenafil therapy, the effect was more pronounced and longer lasting, and the vasodilatory response was greater. Beraprost with sildenafil resulted in a more potent lowering the disease and a longer treatment effect.
Sildenafil shows promise as a useful therapy in numerous case reports of PH from a variety of causes. Such as pulmonary thromboembolic disease, pulmonary fibrosis associated PH, heart failure, cardiac surgery, and cardiac transplant, pediatric patients with PAH, portopulmonary hypertension, hemolysis-associated PAH, and HIV-associated PAH. Over the last two decades, sildenafil made enormous progress in the treatment of patients with PH resulting in significant improvement in morbidity and mortality. However, some studies say treatment with oral sildenafil 40 mg t.i.d. for 6 months in patients with persistent PH after successful correction of LHD-PH due to VHD is associated to unfavorable clinical outcomes as compared to placebo.
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