Phosphodiesterase-5 inhibitors in management of pulmonary hypertension: Safety, tolerability, and efficacy

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease that causes severe disability and has no cure. Over the past 20 years, a variety of treatment options have evolved for the management of PAH. With an expanded therapeutic armamentarium come more complex decisions regarding treatment options. Agent selection depends upon several factors including efficacy, side effect profile, and cost, as well as convenience of administration. We have undertaken a review of phosphodiesterase-5 (PDE-5) inhibitors in PAH with a focus on efficacy and safety. A literature search was conducted using the Medline and Cochrane Central Register of Controlled Trials databases (1966–February 2010) for relevant randomized clinical studies. Overall, 10 studies met our inclusion criteria. Sildenafil was the most commonly studied agent, followed by tadalafil and vardenafil. Most trials found that the PDE-5 inhibitors significantly improved exercise capacity and lowered pulmonary pressures. However, there were conflicting results regarding these agents’ impact on improving cardiac function and functional class. Overall, these medications were effective and well tolerated with a relatively benign side effect profile. The PDE-5 inhibitors are an important option in treating PAH. While most of the published clinical data involved sildenafil, the other PDE-5 inhibitors show promise as well. Further studies are needed to determine the optimal doses of this therapeutic drug class, as well as its effects as adjunctive therapy with other agents in PAH.

Reported Sildenafil Side Effects in Pediatric Pulmonary Hypertension Patients

“…In the longer follow-up analysis of the randomized patients, the adverse effects were consistent with known side effects: headache, dyspepsia, diarrhea, and blurred vision ( 2 ). In a Cochrane review of 10 randomized studies of all phosphodiesterase-5 inhibitors approved for treatment of PAH in adults, headache was the most common side effect in a dose dependent fashion, followed by flushing and myalgias ( 6 ). Similarly, in combination therapy with epoprostenol, reported side effects were headache, dyspepsia, pain in extremity, and nausea ( 3 ).…”

Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

“…It is well known that PDE5A regulates vascular smooth muscle contraction by controlling the intracellular cGMP level, especially in penis and lung. Thus, pharmacological inhibition of PDE5A activity is in clinical application for treatment of erectile dysfunction and pulmonary arterial hypertension (PAH) using 8 (sildenafil, Viagra™), 9 (vardenafil, Levitra™), tadalafil (Cialis™), and avanafil (Stendra™) [9,20,32,88,89,90]. Additionally, an increased myocardial expression of PDE5A in advanced heart failure has been reported [91].…”

“…In the case of [ 11 C] 11 , radiolabeling has been performed by esterification starting from a carboxylic acid precursor [97]. The retention of these radiolabeled derivatives in lung, which is the tissue with most abundant PDE5A expression [34,87,89], has been the main criterion for their suitability as radioligands for PET imaging of this enzyme [97].…”

The practical management of fluid retention in adults with right heart failure due to pulmonary arterial hypertension

“…Phosphodiesterase-5 inhibitors approved for the treatment of PAH include sildenafil and tadalafil. Neither have a listed incidence of peripheral oedema nor have been associated with oedema in clinical trials 40 . Similarly, peripheral oedema is not a listed adverse event of the sGC stimulator riociguat 41 .…”