Effect Measure

The Erectile Dysfunction (ED) drugs already carry the required warnings we know from our misspent youth: Warning: you can go blind doing this. Okay, it says you may experience sudden loss of vision. Same thing. Now a new warning is being added: Warning: it might make you hard — of hearing:

The impotence drugs Viagra, Cialis and Levitra will get prominent warnings on the risk of sudden hearing loss, U.S. regulators said.

[snip]

The FDA found 29 reports of sudden hearing loss in people who took the erectile dysfunction drugs since 1996. More than 40 million people worldwide have used the medications, said Robert Boucher, an FDA medical officer, in an interview. The agency isn’t sure whether the drugs caused the hearing loss and is continuing to investigate, he said. (Bloomberg)

Last week our Scibling Mark Hoofnagle at Denialism Blog had a terrific post on the history of ED treatments. Included was the report of Giles Brindley’s notorious 1983 lecture to the British Urodynamics society that . . . well you have to read it and see why Mark calls it the most outrageous medical talk — ever. We’ve also discussed the physiology of this a bit here in connection with some studies being done on rats which involved injecting their penises with a peptide. Little did we know at that time that Professor Brindley had scooped them in the penis injection department, all in the great tradition of self-experimentation. Exhibiting the raw data was not part of the tradition, but go read it for yourselves.

The physiology of these drugs is interesting, though. On arousal, nerves in the penis release the neurotransmitter nitric oxide, whose chemical formula is NO. In this case, NO really does mean Yes, Yes, Yes. NO release starts a cascade of chemical reactions culminating in the production of a chemical messenger, cyclic Guanosine Monophosphate (GMP; this is also an abbreviation for Good Manufacturing Practice. Make up your own jokes.). cGMP affects ion channel conductance, meaning it opens and closes membrane gates that let ions in and out of the muscle cells, resulting in relaxation of the smooth muscles that restrict the flow in penile blood vessels. The blood then flows into and expands a spongelike tissue in the penis, producing an erection. As long as the cGMP hangs around (if I may use that phrase in this connection), so will the erection.

A permanent erection makes jogging more difficult, so the male body has a way to degrade cGMP, thus shutting down the blood flow into the spongy tissue. An important enzyme in the degradation is phosphodisterase-5 (PDE-5). Viagra and the othr ED drugs inhibit PDE-5. It doesn’t give the (male) person an erection, but helps maintain it. In a sense, while you may think of an erection as the system being “on,” with regards to smooth muscle it is “off.” PDE inhibitors like Viagra don’t flip the switch but if it gets flipped to the smooth muscle “off” position it stays there until the PDE inhibition goes away. A condition of “priapism” (prolonged erection) means you can’t flip the switch back to “on,” the smooth muscle cell around the blood vessel contricted (and hence end of erection).

Chemical signaling by cGMP is not confined to the penis. cGMP is an important “second messenger” in a number of other systems (and also affects metabolism). In the eye, “dark” causes high cGMP in the rods and cones (light and color sensitive cells in the retina). Light sets in motion a chain of events that has PDE as part of it. I have simplified the events enormously, but the point is that both cGMP and PDE are also involved in photoreceptors. cGMP keeps photoreceptors depolarized, so the position of the ion conductance gates produces a “dark current.” The dark current is like the stimulus that keeps the smooth muscle in the penis arteries contracted. If the cGMP can’t be modulated up and down then you stay “in the dark” as far as the photoreceptor cells are concerned. When the switch is flipped into the “dark” position, apparently the PDE inhibitors in some cases prevent it from being flipped into the “light” position. How and why this happens in some men taking
ED drugs isn’t known or why it only affects a few. Blind luck, I guess.

cGMP apparently plays a role in auditory processes, too, which might explain the reports of sudden hearing loss. A quick search of the literature showed some work on insect auditory systems dissecting the role of cGMP but I didn’t find a lot, although I didn’t look that hard. If some portion of the auditory system requires a change in polarization of nerve cells mediated by cGMP, presumably the same kind of thing could happen. At this point the drug companies are saying the connection with ED drug use is coincidental.

Maybe it’s just sudden hearing and vision loss on the part of their lawyers.

Comments

#1 sailor
October 20, 2007

Interesting and amusing post, now as an exercise we have to figure out how this same thing causes the other side effects:
Headache, 16%, and I wonder how many males go ahead anyway?
Flushing 10% (and I don’t think they mean the toilet)
Dispepsia 7%, nasal congestion 4%
In order to make sure you you did not worry about these side effects too much they also gave the placebo rate for them. I had to look further to find the placebo rate for the effectivness of Viaga itself (seems likely placebo would not be bad). Turns out the drug itself will not work at 50mg levels in about quareter of the the population. And for a quarter of the population chalk pills work just fine. Leaving half the population to get real benefit.
#2 marquer
October 20, 2007

And, sadly enough, the typical aging male with difficulty getting a mutually satisfactory erection is having that problem simply because his testosterone levels have fallen sharply.

Supplemental testosterone solves that at once in most cases. Supplemental testosterone doesn’t cause vision loss. It doesn’t cause hearing loss. It doesn’t cause headaches or congestion. It has remarkable puissance against the unipolar depression which frequently afflicts men beginning at andropause, said disorder being invariably underdiagnosed due to the cultural reluctance of most men to discuss personal emotions with a clinician.

Supplemental testosterone further appears to exert substantial cardioprotective effects (note that men in midlife start to have coronaries right about the time that their endogenous T levels plummet). It is increasingly apparent that even in the case of prostate cancer, where testosterone was long thought the villain of the piece, the cause is instead linked to the things which testosterone aromatizes into. Easy enough to block that process.

So why does our medical-industrial complex not simply prescribe such men supplemental T? Because the profit margins for such therapy would be far less than they are with these demonstrably dangerous phosphodiesterase inhibitors. Testosterone cypionate is off-patent and dirt cheap, and has an enviable track record of clinical safety.

Yet another case of a systemic mandate for medicine that is deliberately inferior and deliberately more expensive than need be.

–
#3 daedalus2u
October 21, 2007

I think that some of the side effects of Sildenafil have to do with non-cGMP effects of nitric oxide. In particular the exacerbation of obstructive sleep apnea,

http://archinte.ama-assn.org/cgi/content/full/166/16/1763

likely occurs because by blocking PDE5, the feedback of the NO regulatory system is affected, and (no doubt) physiological pathways not involving cGMP don�t work as well, such as the regulation of breathing via RSNOs

http://www.nature.com/nature/journal/v413/n6852/full/413171a0.html

This relates to my research on basal levels of NO, where because all NO sensors only sense the sum of NO from all sources, a change in the basal level affects all NO mediated pathways with no threshold. That is because NO is already in the �active range�, any change in the basal level will affect the output of that feedback regulated pathway.

Another important pathway regulated by NO is the ATP setpoint via sGC and cGMP

http://www.pnas.org/cgi/content/full/101/1/37

If Sildenafil affects NO feedback, it will affect all non cGMP pathways with no threshold.
#4 stu
October 24, 2007

29 reports out of 40 million users, each who presumably have taken it on multiple occasions. Is this saying the effect is around 240 PPB? Or less? Also, is there a similar occurance for say, aspirin? I am just wondering, I have zero experience in drug trials so maybe you guys could weigh in.

Ditto on the testosterone, no matter how well you take care of yourself there is the inevitable decline. Too many side effects though, plus I’m not sure if we are supposed to go through life with 18 year old libido levels.
#5 revere
October 24, 2007

stu: The reported cases are small. This is the reason we need post market surveillance because you could never pick this up in a drug trial (too rare). However it is important to know about it, so warnings are placed.
#6 stu
October 25, 2007

Yes, it’s great that they report and note the effects. But, I tend to look at the chances that I would experience a certain side effect, but many people will simply avoid a medication because of it.

Sort of a tough call in life, just about everything we do involves a potential risk. Like vaccinations.
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