PDE5 inhibitors are generally well tolerated, with side effects including transient headaches, flushing, dyspepsia, congestion and dizziness. There have also been reports of temporary vision disturbances with sildenafil and, to a lesser extent, vardenafil, and back and muscle pain with tadalafil. These side effects may be attributed to the unintended effects of PDE5 inhibitors against other PDE isozymes, such as PDE1, PDE6 and PDE11. It is theorised that improved selectivity of PDE5 inhibitors may lead to fewer side effects. For example, vardenafil and tadalafil have demonstrated reduced adverse effects probably due to improved selectivity for PDE5. However, no highly selective PDE5 inhibitors are currently in development.
Patients who take nitrates, alpha blockers or sGC stimulators within 24 hours of PDE5 inhibitor administration (or 48 hours for tadalafil) may experience symptomatic hypotension, so concurrent use is contraindicated. PDE5 inhibitors are also contraindicated in patients with hereditary eye conditions such as retinitis pigmentosa due to the small increased risk of nonarteritic ischaemic optic neuropathy in patients taking the medication.
Hearing impairment is one risk factor for those who are using PDE5 inhibitors and it has been reported for all available drugs on the market. This problem may be due to high level effect cGMP on cochlear hair cells. It has been reported that PDE5 inhibitors (sildenafil & vardenafil) cause transient visual disturbances likely due to PDE6 inhibition.
Several reports are about approaches to improve PDE5 inhibitors, where as chemical groups have been switched out to increase potency and selectivity, which should potentially lead to drugs with fewer side effects.