Sildenafil (Viagra) may not be safe in Retinitis Pigmentosa

Sildenafil (Viagra) is a PDE5 inhibitor in wide use for the treatment of erectile dysfunction. It is known to increase the level of cGMP, and ultimately increases penile response to sexual stimulation. Sildenafil preferentially inhibits PDE5 more than PDE6, both of which are expressed in the retina. Therefore, there is a potential for this drug to alter retinal function, not only in normal subjects, but also in patients with PDE6 gene mutations such as in some forms of RP. 

Visual side effects of sildenafil in humans, referenced in Investigative Ophthalmology and Visual Science, include temporary occurrence of blue-tinged or hazy vision and an increased sensitivity to light. These phenomena increase with dosage, with the incidence approaching 50% if recommended dosages are exceeded. Studies published in The Lancet and Survey of Ophthalmology evaluating retinal function in humans by electroretinography have noted small transient changes to the electroretinogram (ERG). Such investigations have focused on normal subjects rather than those with underlying retinal diseases. Little information is therefore available on the potential side effects of sildenafil in patients with frank RP or in carriers.

Sildenafil, the active ingredient in Viagra, has been reported to cause transient visual disturbance from inhibition of phosphodiesterase 6 (PDE6), a key enzyme in the visual phototransduction pathway. This study, published in Experimental Eye Research, investigated the effects of sildenafil on the mouse model for carriers of Retinitis Pigmentosa. Such carriers exhibit normal vision but may have a lower threshold for cellular stress caused by sildenafil due to a heterozygous mutation in PDE6.

In this study, Sildenafil caused a dose-dependent decrease in electroretinogram (ERG) responses in normal mice, which mostly recovered two days post administration. In contrast, the mouse model that simulated RP carriers exhibited a significantly reduced photoreceptor and a supernormal bipolar cell response to sildenafil within 1 hour of treatment, while taking two weeks to return to baseline levels. This suggests that sildenafil has direct effects on both the inner and outer retina and these effects differ significantly between normal and carrier mice. There was an increase noted in expression of the cytochrome c in the mouse model of RP carriers. Presence of cytochrome C, an early apoptotic marker, in the mouse model indicated that the effects of sildenafil on visual function may potentially lead to degeneration. The results of this study are significant considering approximately 1 in 50 people are likely to be carriers of recessive traits leading to retinal degeneration.

Recessive retinitis pigmentosa patients usually have two copies of the mutant PDE6 gene. However, there are also carriers of the disease who have just one copy of the faulty gene, yet have normal vision.

Pattern of autosomal recessive RP inheritance (Credit: Current Genomics)

Dr Nivison-Smith, the lead author in the paper said in an interview that her team is concerned that Retinitis Pigmentosa carriers, who carry a single copy of the mutant PDE6 gene and who have normal vision, may be more susceptible to changes caused by sildenafil. The way erectile dysfunction drugs work to combat impotence may also inhibit PDE6, an enzyme which is important for transmitting light signals from the retina to the brain. This is likely to be a problem for such carriers, because they produce less of the enzyme than normal.