Abstract
PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.
Highlights
| INTRODUCTIONDeveloped over 30 years ago, initially for cardiovascular indications, PDE type 5 inhibitors (PDE5Is) emerged as a revolutionary treatment for erectile dysfunction (ED), licensed in 1998 (Goldstein, Lue et al, 1998)
PDE5 is abundantly distributed in vascular smooth muscle, PDE5 mRNA and isoform expression has been identified in various human organs, including brain, lung, heart, liver, kidney, bladder, prostate, urethra, penis, uterus and skeletal muscle, where it performs numerous physiological functions mediated by the NO–cGMP pathway (Figure 2; Boswell-Smith, Spina, & Page, 2006)
A recent meta-analysis of six randomised controlled trial (RCT) that included 244 patients with secondary Raynaud's phenomenon (RP), predominantly due to scleroderma, found that PDE type 5 inhibitors (PDE5Is) therapy moderately reduced the daily frequency and duration of vasospastic attacks and promoted visible healing of ulcers (Roustit, Blaise et al, 2013) and a prospective crossover study suggests that these beneficial effects extend to primary RP (Caglayan, Huntgeburth et al, 2006). These findings suggest that PDE5I therapy may have an equivalent effect on vasospastic attack frequency to first-line treatment with calcium channel blockers (CCBs) and is more successful at reducing attack frequency and promoting ulcer healing than ET receptor antagonist (ERA), an effective and approved treatment for reducing digital ulceration in scleroderma but which has inconsistent or minimal effects on other clinical parameters and is of uncertain benefit in primary RP (Roustit, Blaise et al, 2013)
Summary
Developed over 30 years ago, initially for cardiovascular indications, PDE5Is emerged as a revolutionary treatment for erectile dysfunction (ED), licensed in 1998 (Goldstein, Lue et al, 1998). Further investigation of their effects on pulmonary arterial pressure culminated in their approval for the treatment of pulmonary arterial hypertension (PAH) in 2005 (Galiè, Ghofrani et al, 2005). Reports of fatal cardiovascular events in patients prescribed a PDE5I delayed wider research into their therapeutic benefits, but it soon became apparent that these adverse events reflected the complex nature of patients initially receiving the drug and their high level of cardiovascular risk, rather than the properties of the drug itself (Cheitlin, Hutter et al, 1999; Giuliano, Jackson et al, 2010).
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