Viagra and vision loss




You'll go blind! so the joke goes. It turns out that Viagra, Cialis etc... are alleged to be involved with vision loss in some patients which is something that we predicted might happen a few years ago. My wife told me this morning that this issue is finally starting to make it around to the popular media, but I first heard about this possibility several years ago when my mentor and I were talking about phototransduction and phosphodiesterase inhibitors.

The mechanism for vision loss that everyone is talking about is called non-arteritic anterior ischemic optic neuropathy and can occur in men who have diabetes or heart disease, which are two conditions that typically can lead to impotence and therefore may cause these same patients to seek out assistance. This of course is why drugs like this are prescription drugs and should be carefully monitored and administered by physicians.

However, this form of blindness is not what I am concerned about and I think these are two separate issues that perhaps are being missed by the community as a whole. Viagra, Cialis and Levitra are "selective" phosphodiesterase inhibitors. I put that in quotes, because they apparently are not that selective and have some degree of overlap with another phosophodiesterase involved in vision. Specifically, there is a 10:1 selectivity ratio for PDE-5 over that of the closely related PDE-6 enzyme that we will get to in a minute. So the intended mechanism for these drugs is: Sexual arousal leads to increased parasympathetic activity which results in production of nitric oxide (NO). NO activates the enzyme guanylate cyclase which increases cGMP concentrations. cGMP acts by dilating the smooth muscles in blood vessels which results in increased blood flow and.....enlargement. Normally, cGMP is then degraded by the enzyme phosphodiesterase5 (PDE-5) and in the absence of maintained NO synthesis, vasodilation is reduced, reversing the whole process. These drugs work on PDE-5, preventing its inactivation which results in a prolonged activity of PDE-5 and therefore, prolonged vasodilation. The problem is with this lack of selectivity issue. As discussed above, these drugs also inhibit a closely related phosophodiesterase enzyme, phosphodiesterase6 (PDE-6) which is found in the retina and plays an important role in the normal visual transduction cascade.

In vision, cGMP will keep Na+ channels open in the membranes of your photoreceptors. Photons when they hit the photoreceptors, are absorbed by another molecule called 11-cis retinal which causes a conformational change to a trans retinal form. Activated rhodopsin at this point catalyzes the conversion of GDP to GTP which then activates the transducin protein. Transducin contains multiple subunits including an alpha subunit which breaks off when activated. The activated alpha subunit breaks away from the beta and gamma subunits of transducin and then "pulls away" the inhibitor from PDE-6. At this point PDE-6 then converts cGMP to 5'GMP whereupon the reduced cGMP levels allow for Na+ channel closure. If Viagra inhibits PDE-6, the channels in photoreceptors are constitutively open which means they never shut down.

This explanation over coffee this morning Led my wife, H to quip: "wow, so you pop a rod and you pop rods!", which was not entirely true, but it was sufficiently funny for me to almost launch my latte out of my nose.

Seriously though, there are certainly visual alterations reported with the use of these drugs including vision with a blue tint, difficulty distinguishing between blue and green light and light sensitivity. In fact, pilots are prohibited by the FAA from flying within 12 hours of using Viagra. These of course are short term problems, but there are issues that should cause some concern. Notably, there are defects in PDE subunits that are associated with a form of retinal degeneration called retinitis pigmentosa or RP (the group of diseases that much of my doctoral dissertation was about). Additionally, there are defects in the cGMP gated cation channels that are also associated with RP. If the biology and pharmacology of these drugs mimic the issues that are functionally related to aberrant activity of these diseased proteins, then we may have a problem.




Posted: Fri - May 27, 2005 at 10:52 AM          

©