This Podcast Will Kill You - Ep 167 Viagra/Sildenafil: Raising the bar

Episode Date: February 25, 2025

Has a name brand prescription medication ever shot to notoriety as quickly as Viagra did? Within a few months of its arrival on the market, it seems like everyone knew about the little blue pill, whether through commercials featuring celebrity spokespeople or from endless jokes on late night talk shows. But while everyone understood that this medication promised to treat erectile dysfunction, what most people didn’t know was the wild story leading to its development. Or how this medication (and similar medications) actually works. Or the tremendous impact this blockbuster drug would have on the ways that medications are advertised and developed. In this episode, we bring you those stories (and many more). Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAuSee omnystudio.com/listener for privacy information.

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ED, often called impotence. You know, it's a little embarrassing to talk about ED, but it's so important to millions of men and their partners that I decided to talk about it publicly. And after all, it can be associated with many conditions, including prostate surgery, high blood pressure, diabetes, or diabetes. even smoking. The point I want to make is that there are many treatments available for ED. So my advice is to get a medical checkup. It's the best way to get educated about ED and what can be done to treat it. It may take a little courage, but I've always found that everything worthwhile

does. I mean, none of it was wrong. I love it. It's because it sounds more like a PSA than an advertisement. It does. It totally sounds like it. I mean, they don't even say the name of the medicine, right? It's very under the radar. Uh-huh. So that was from the infamous, really historic Bob Dole, commercial from 1998? Bob Dole, Bob Dole, Bob Dole? Do you know that was one of my brother's first words? Was he born near, like in the year leading up to a presidential election or what? I don't know. I just remember during the presidential election, I'm pretty sure it was. my youngest brother. It might have not even been him, but sitting there saying, Bob dole, Bob dole, Bob dole. So it could have been the one who was 1990. I don't know.

That's someone who's watching too much TV and too many political commercials. Right. Bob dole, Bob dole, Bob dole, anyways. Oh, man. Yes. Well, hi. I'm Aaron Welsh. And I'm Aaron Omband Updike. And this is, this podcast will kill you. And today we're talking about Viagra. We are. Can we say trade names? We're talking about syldenafil. We're talking about Viagra. I mean, my part is mostly about Viagra. Okay, great. So like Viagra is also not the first trade name that we would have said on this podcast.

No, I mean, we spent the whole allergies episode talking about epipens. Yeah, exactly. Epinephrine auto injectors. Right, exactly. Too much to say. It's going to be a great episode. It's going to be a great episode. I am so excited for this one. Yeah. There's just, it's a, it's a rich topic. Yeah. Rich. Who knew? Who knew? Yeah. We should have. We did. We did. That's why we picked it. Yeah. But before we get into all of that, Aaron, what time is it? It's quarantini time.

It is. And what are we drinking this week? Nothing other than Little Blue Pills. Yep. It makes sense. It makes sense. P-I-L-S, just one L. Just because it's a beer. It's a beer drink. It's a Pilsner drink even. And lemonade and blue Curacao. Sorry.

Sorry, but not that sorry, because it's clever. I mean, we had to do the name, and then the recipe was based on that. Exactly. And so there you go. Enjoy it. Or don't. Yeah. Anyways, you'll find the full recipe so you can decide for yourself.

For that quarantini and the non-alcoholic will do it, Plissie Barita, on our website, this podcast will kill you.com and on all of our social media channels. And on our website, you can find all sorts of goodies, including but not limited to transcripts, links to our bookshop.org affiliate account, our Goodreads list, music by Bloodmobile, links to a first-hand account form, a contact us form.

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This podcast will kill you.com. If you haven't already, please remember to rate review and subscribe on whatever podcaster you like to listen to so that you don't miss our new episodes and because it helps us get up in the charts, which helps new listeners find our podcast. So thanks. We appreciate it. Mm-hmm. Erin, can we get started with today's topic?

Right after a short break. Sildenafil is the medicine that we're talking about today, and it is, of course, most famous for its use as a treatment for erectile dysfunction under the trade name Viagra. But that is not its only use. So I want to give credit up front that this is also an important medication that is used for the treatment. of things like pulmonary hypertension in both adults, but also tiny babies off-label use. And that's a condition where the pressure in your blood vessels and your lungs is too high, and it can make it really difficult to breathe. In babies, this is often because they're born premature. But I'm saying that now because that's mostly the last time I'm going to talk about it.

Because its use in other contexts is really overshadowed, of course, by its fame as Viagra. So to understand the use of this medication in the treatment of erectile dysfunction, we have to start by talking about erections. What are they? How do they work? What is happening when they don't work? And why does Viagra help? So we shall begin. All of the questions that we should be asking. Exactly. There is the potential, as evidenced by multiple like 20 to 50 page papers on the detailed biochemical reactions and the neurobiology and endocrinology of what's happening in a penile erection. There's the potential to go into way too much detail. But for this episode, I will link to all of those papers so people who want to dig deep can. What we need to understand is really the broad

strokes of what an erection is. A penile erection is the end result of a pretty complex neurovascular process, which means that it involves a real web of our peripheral nerves, as well as our brain and spinal cord. It involves both sensory and motor nerves, and both our sympathetic and parasympathetic, so those autonomic nervous systems. It coordinates through tactile, auditory, visual and other stimuli, and involves a pretty wide range of neurotransmitters as well as hormones, and all of this has to coordinate with our vascular system, which is what deals with blood flow in and blood flow out. And we don't have to get deep, deep into the details to understand how this works and how Viagra, sylennephyl, can affect this process. But we do need to understand

the anatomy of a penis. So anatomical. The penis has some pretty specialized tissue, creatively called erectile tissue. Wow. Okay. I know. Such creative naming. So if you were to look at the interior of a penis, like in cross-section, to me, it kind of looks like a fly with like an open mouth going like, oh, okay? Because, like, imagine a fly, a big fly eyes.

But then they have like a human mouth going like, oh, my gosh. I don't like that image, but continue. But it's in your brain now. So in cross-section, it has these two big round, almost really they're like tubes that are full of this spongy type of tissue that's called the Corpora Cavernosa. And each of these, Corpora Cavernosa, has an artery that flows through the center. And then these two sponges are surrounded by a. pretty dense, fibrous tissue that forms a sheath, like a sword with a sheath, right? It's a firm area. And that is what looks like the fly eyes, like this pair of big, wide eyes. And then

beneath that, like on the dorsal underside of that, if you're looking at a cross-section, there's another tissue spongy tissue tube called the corpus spongiosum. And inside this tube is the urethra, where pee is going to come out as well as ejaculate is going to come out. And that's what looks like the mouth of the fly. This is surrounded by a thinner fibrous sheath of tissue. And then the whole thing is surrounded by a lot of different smooth muscle, not skeletal muscle, but smooth muscle. So just like a lot of different types of tissue all layered together. A lot of different types of tissue in these three pockets of sponges. area. Okay. With a lot of smooth muscle tissue all up in there. And smooth muscle is the type of muscle

that we have all over our bodies. It's what surrounds our arteries or is part of our arteries. It's what's in all of our internal organs except for our heart, which has its own specialized kind of muscle. But unlike most other smooth muscle in our bodies, the smooth muscle that surrounds the corpora cavernosa in the penis, is tonically contracted, which means that it's always a little bit, though not 100% completely, but it's a little bit clamped down, contracted rather than relaxed. And what that does is it allows for only enough blood flow through to keep the tissues of the penis healthy without allowing too much blood in. So what happens in an erection through, again, this complex series,

of neurotransmitters, hormones, blah, blah, blah, is that this smooth muscle starts to relax. And that causes the dilation of those arteries in the corpus cavernosa, in those flies' eyes, and that allows for increased blood flow. That blood flows out of the arteries into those tissues and fills up all of this spongy potential space. These are called sinusoids,

and they're basically like chambers in those spongy tissues. And as those tissues begin to expand, they actually compress the veins in the penis, which are all located outside of that fascial tissue or in between layers of fascia, but outside of those sponges. So it's like let more blood in and prevent blood from leaving. Exactly, exactly. And that traps the blood in those sinusoids, the sponge, you have very little venous outflow, and the more that that process continues

through this kind of positive feedback loop, then eventually you have a really significant increase in the pressure inside of the penis, and then you have a contraction of nearby muscles called the ischia cavernosis muscles, and these are muscles like in the pelvic floor, not smooth muscles, but skeletal muscles, and that provides a further, rigidity. So you have, that's how you end up with the rigidity of an erection. Does that make sense? Yeah. That's it. That's all it is. We can make it as simple as that. More blood in, less blood out. Erection. Erection. And to do that, you first need a relaxation of that smooth muscle. So then, if we understand that, then we can understand that there's a lot of ways that this process

could go wrong. And that end result is called. erectile dysfunction. And for this, I'm going to just rely on NIH definitions, limited though they may be, erectile dysfunction is the condition in which somebody cannot either achieve or maintain an erection that is firm enough for a satisfactory sexual experience. That's the literal definition. And there isn't one underlying cause of erectile dysfunction. Irrectile dysfunction is an end result, right? It's a dissatisfying sexual ability or the inability to have the satisfying sexual experience because the erection is not as firm as either it used to be or as you want it to be. Now, again, there's limitations to this. And one thing that I'm not probably doing a good enough

job in this whole episode is going into the nuances of how we define sexual health in general. Right. Or what is a satisfactory sexual experience? Exactly. Right. Yeah, yeah, yeah. Right. So, like, that is beyond the scope of this. But if we're sticking with this definition, then what we're looking at really is that erection itself. And there's a lot of different things that can end up causing erectile dysfunction or a lot of different risk factors that end up relating to this, right? There are, of course, psychosocial issues, like we said, like what is healthy sexual function? What does it mean to that? individual, what's considered disorder, but if you accept that I've got a disorder or I feel like there's a disorder, there's a lot of different things that can end up causing this. There's things like neurologic issues, whether that's a spinal cord injury or peripheral nerve damage, or either like demyelinating disease like MS, or a whole host of other chronic diseases that can cause nerve issues. There's also endocrine issues, like low levels of testosterone,

own. There's also vascular issues. And vascular issues likely account for the majority of erectile dysfunction, though it's a little hard to get great stats on this, but a lot of papers estimate like 70% or so. And vascular disease is not one thing, right? There's a whole bunch of risk factors that lead to vascular disease that can lead to erectile dysfunction. Diabetes, high blood pressure, high cholesterol, all of these affect the lining of our blood vessels, which is going to affect blood flow, which is necessary for an erection. Aging in general causes oxidative stress and endothelial dysfunction. And then, of course, the hospital can do it to you, which it sounds like was what happened in our first hand account because someone had treatment for cancer.

I was like, what do you mean? Treatment for something like prostate cancer or other operations or medications that can sometimes cause erectile dysfunction. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no meal planning and no extra grocery trip. There, assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients on a sheet pan, put it in the oven, and that's it.

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What is the aging? Why does the aging process lead to higher rates of ED? Aaron, this is a question. that made, like, I already was, I wondered this, but looking at the statistics, I wonder even more. Because, okay, this is jumping ahead, but statistically, people say that anywhere from like 50 to 100% of people with a penis over age 70 have erectile dysfunction. Okay. Again, meaning that they're not having a satisfying sexual experience because they're not able to achieve or maintain an erection. Which, real quick, again, does that definition include frequency? Is that every time? Is that just one,

once in a month? Is that once in a week? Like... It doesn't include any of that. It doesn't matter, right? Because it is subjective. It is a subjective experience that is meeting criteria for this dysfunction or disorder. Right. It's giving me menopause vibes where we're calling this a disorder because it is causing impact on your life, which is valid. Right. But is it a disorder like evolutionarily? Maybe not, right? I don't know. Wait for it. Just wait for it. There's more where that came from.

We'll get into it. I can imagine. Because again, it is very individual. Like, what is the satisfying sexual experience for one person is not the same as for another person? For some people, it might not even include an erection. It might not even include orgasm. Like, there's so much nuance to this. What's the end goal here for, yeah, exactly.

Fixing, fixing this, quote unquote, fixing. This. Fixing this. And in this, in the case of erectile dysfunction, is just the firmness of the erection. But there is a real relationship between age and ED. So what is going on mechanistically? Like, what is the basis for this physiologically? Great question.

I don't have a one single answer for you. I don't have like an aging equals this. There's a lot. There's the fact that as we age, all of those other risk factors go up. cholesterol goes up, blood pressure goes up, the rates of diabetes go up. Aging also, like I said already, is thought to be independently associated with things that end up causing endothelial dysfunction, which is blood vessel dysfunction. Is it just that? There's a lot of different factors. I don't think that there's one thing that aging causes that leads directly to erectile dysfunction.

I think it's a whole host of issues. I just have so many questions, but keep going. I don't know that I'm going to answer any of your questions, but out of all the different things, be they neurogenic, be they vascular, be they psychological, be they hormonal. Very often, the first thing that is used for treatment is one thing, and that is Viagra. So no matter the cause, that's not usually investigated, first thing, often not even second thing. the treatment is a blanket Viagra for all your woes. And so what percentage of cases of ED does Viagra actually help with? Most papers I read estimated 60 to 70%.

Wow, okay. It's pretty high. It's pretty high. Why is that? How does it work? Let me tell you. Sildenafil Viagra. It's a phosphodiasterase or PDE inhibitor.

What does that mean? PDE is an enzyme. It's not one enzyme. It's a whole group of enzymes. And these enzymes are present on a whole bunch of our tissues throughout our bodies. But there's one in particular that Viagra is very strongly, like it really only works on this one type of phosphodiasterase called PDE5. And this particular phosphodasterase enzyme happens to be present in very high concentration in the corpus cavernosum of the penis. That's spongy tissue that's responsible for, the majority really of an erection. So through this, again, very complicated series of biochemistry, the end result of blocking PDE5, which is what sildenophil and other similar drugs do, it blocks the action of this enzyme, and that results in this cascade of events that causes is increased relaxation of that smooth muscle. So that allows for blood flow into the corpus cavernosum to start, and that allows the further steps of an erection to take place. That whole cascade of

things can happen if you have relaxation of that smooth muscle and increased blood flow. And that's it. That's it. It can be as simple as that. What about other ED drugs? So Cialis is the trade name for tadalafil, which you can tell by the afil at the end that it's the same type of medication. It has like a different half-life and blah, blah, blah, but it's still a PDE5 inhibitor. So it acts in the same way. And there's a few other drugs that are really similar, just like different versions, essentially, but acting on the same end time. So all of those work in a very similar way.

There are other medicines that are used. Some of them are like injectable medicines that you inject directly into the penis. Some of them are, you can put them in other ways. A lot of them still, like predominantly we target this phosphodiasterase pathway. The other ones might target different PDEs, so PDE1 instead of five or whatever. But that's predominantly what they're doing is targeting this pathway. Erin, you said injectables and then you said and then put them in in other ways and you just try to skis right by that? Can you go back to that? It wasn't that exciting of other ways. I just mean like

sublingual or, yeah, injectable. I don't think that there are any that are just topical, though I think that that's been tried. Yeah. Okay. Not that exciting. So yeah, I mean, that that is honestly, that's the, that's the basis of it. That's how Viagra works and that's why it works. Interestingly, sildenafil still requires the initial steps of erection, which includes sexual arousal. So you still need first this neurologic input before you get that relaxation of the smooth muscle from sildenafil, because it's not like direct. The way that it happens It's like the buildup of certain precursors and then the blocking of calcium and blah, blah, blah. So syldenafil itself, Viagra itself does not cause an erection.

It also doesn't affect libido or sexual desire. All it does is allow for increased blood flow so that in the context of an erection, it can be firmer and or last longer. Just opens the blood, floodgates, but waits for the signal from your brain. Yeah. It like, it makes the floodbts. gates easier to open. It allows for there to just be like a gentle push instead of like a big shove, like of a heavy door. Okay. So I have a bunch of questions. Okay. All right. You always see you on the commercials if you have an erection lasting longer than four hours, et cetera, seek medical care. Yeah, that's called priapism. Right. Why is that happening? And second to that is

kind of similar to that is like what are some of the other side effects that we see with use of sildenophil and why do we see those things? Great question. So, of course, any medicine has the risk of side effects. Most common side effects with Viagra are things like headache or flushing. You can have some dizziness or, like, stomach upset. Also weirdly nasal congestion. I don't actually know why that one happens.

Most of these have to do with the fact that because this is acting on smooth muscle, and while it is specific to P.D.5, and that is mostly found in the penile tissue, It's also found in some other places. So this can cause relaxation of smooth muscle other places and then potentially drop your blood pressure and that might trigger some of these other symptoms. Really importantly, we see this happen if somebody is also taking a medicine that has nitrites in it, like nitroglycerin, which someone might take if they have angina or like that pain in their chest that's from their heart having blockage, basically. If Viagra and a nitrite is taken together, these drugs actually interact with each other and then cause really severe drops in blood pressure, like potentially deadly, really problematic to take these two medicines together. Otherwise, Viagra and similar medications are actually pretty safe most all the time when priapism happens so that like prolonged erection that can be very dangerous because, again, with an erection, you're having a lot of blood flow through the arteries into the penis and very little blood outflow.

So that pressure can really build up and end up, if it lasts for too long, and you don't have enough blood outflow, you can increase the pressure so much that you can start to damage tissue in the penis. So priapism is very serious. That generally only happens if somebody takes too much of this medication. Okay. At the doses that it's usually recommended, it's very, very, very. very rare to have priapism as a side effect. It's usually from doubling up on doses or it didn't seem like it worked, so I took extra, et cetera. And how is priapism treated? A lot of times,

if it needs to be, it is treated by physically removing the blood from the penis with a large syringe. Any other questions? That's it. Yeah, it's not great. It's not great. There's other kind of trying to calm yourself to reduce that blood flow. Because again, there's a lot of like nervous system input that's going into this. So if you can try and reverse some of that psychologically, sometimes that can help a lot with making that erection D2Mess is called. How do you just be like, okay, don't think about this erection. Don't think about this erection that I've had for three and a half hours. Like, don't think about this. It's very hard. It's very difficult to do. So yes. So that's Viagra. Aaron. That's how it was.

works, that's how you get an erection and how you, that's how it works. Erin, tell me how we figured this out. I cannot wait to hear the story, like the story of Viagra. There are so many stories to tell, Aaron, and I can't wait to get to them all right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented,

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Let the dance begin. Love life again. This is the age of man. This is the age of Viagra. And of course, lest we forget, ask your doctor. I'm sorry. Your face, I cannot. Oh, yeah.

Really trying to embody all of these commercials that we have seen. Thank you, thank you. Literally such a good job. When Viagra hit the market in 1998, it sent shockwaves around the world. Late night talk shows made countless jokes. Cultural commentators wrote article after article about how Viagra would transform sex and relationships. Millions of men. made long overdue appointments with their doctor. Hey, any way you get in the door is great.

Pfizer counted their millions, and other drug companies got to work trying to create their own blockbuster drug. The impact that Viagra has had is huge. It changed the way drugs are marketed. It contributed to the medicalization of sex. It opened up discussions about a formerly taboo subject, sex and older adults, it highlighted gender bias in drug production and insurance coverage and research. I don't think the world had seen a drug like it before in terms of how much controversy and discussion it prompted. Its release reminds me actually a lot of the chatter and hype around OZemPEC and related drugs, which we should really do an episode. And this sort of like, this will save us or this will be the end of us, extreme perspectives. Like everything is so like, whoa, this is the end of relationships.

Oh, this is the age of a new era. You know, like that kind of thing. Wow. Yeah. Also, 1998. I don't think I realized it was so recent. Oh, yeah. Yeah.

Okay. I can't wait. And it just slipped into like our cultural consciousness. Right. Yeah. Yeah. Weird. Okay.

But before there was Ozempic, there was Viagra. And before there was Viagra, there was. Nothing? That's the story that you've likely heard and the story that Pfizer seems to love to tell. Nearly every publication that references the origins of Viagra uses the word serendipity, or one of its synonyms. As the story goes, Pfizer was testing out a new drug for a heart condition and stumbled on to greatness by utter chance. That might be part of the story, but it's certainly not all of it. The truth is that the hunt for an erectile dysfunction cure had long been underway. And I'm not talking about herbal extracts or animal glands, which like millennia, people have been using those or trying

those out. I mean that there had been since at least the 1970s and 1980s a real concerted effort in medicine to create a medication, a device, or a surgery to treat what had long been known as impotence but was getting rebranded as erectile dysfunction. The history of impotence is a separate topic entirely, but relevant to this discussion is what people thought caused it throughout that history. And that was your brain. For much of modern medicine, impotence, as it was then known, was considered a condition primarily of psychogenic origin, meaning it was caused by your brain. Anxiety, stress, depression, your wife's frigidity. Yeah, that was one of the leading causes.

Frigidity? Frigidity. Mm-hmm. Cool, cool, cool, cool. And accordingly, it was treated by the folks who dealt with your brain, psychologists and psychiatrists. This notion replaced the previous dominant concept that impotence was a normal part of aging. Hmm. And it began the shift in seeing impotence as something to treat, as something to manage, as something to cure.

It redefined what, quote-unquote, normal looked like. Hmm. People did recognize that there were some cases of impotence that seemed to have a physical or organic origin, but the most commonly cited statistic, which by the way, no one can really figure out where the statistic came from, up until the 1970s or even the 1980s, was that at least 90% of cases of impotence were psychological in origin. Yeah. Compare that to today, which is basically the reverse, quote, Current medical consensus on erectile dysfunction is 10 to 30% psychogenic and 70 to 90% organic, end quote.

And I don't know where they're getting those numbers either. Pfizer. All of it, yeah. All of it is very interesting. Mm-hmm. Mm-hmm. And doesn't even get into like female sexual dysfunction, which is still considered psychogenic and entirely in your brain.

Right. Yeah. But cool. What happened to cause this reversal? Yeah. It wasn't Viagra. Or at least it wasn't Viagra alone, since the tides began to turn at least a decade or two before the drug came on the scene. It was Viagra's predecessors that helped to transform impotence into erectile dysfunction.

Devices, surgical treatments, or even injectable medications that were developed and tested in the 1970s and 1980s showed that, for at least some men, erectile dysfunction could be treated with medical rather than psychological intervention alone. And this led to a shift in who treated erectile dysfunction, as it was beginning to be known, from therapists to urologists, as well as increased interest in the physiological basis of erections and ways to induce them via medication. Which brings me to the story of Professor G.S. Brindley. Okay. Have you heard this story?

Nope. Okay. Name doesn't sound familiar? Nope. Okay. Should it? By the end of this, I won't forget it. Yeah, I think that's sort of how I feel.

It's now scarred into my brain. Okay. Nothing could have prepared me for this. Oh, dear. Oh, my God. Let me set the stage. Yeah, no, truly. The year, 1983.

The location, Las Vegas, aka Sin City. The occasion. the annual meeting of the American Urological Association. Hot stuff. On this fateful day, referenced in every history of Viagra article and book, Professor G.S. Brindley made his way to the lecture hall, where he was scheduled to give an evening talk titled something along the lines of

vasoactive therapy for erectile dysfunction, something innocuous, unremarkable. The audience was not substantial, around, 80 or so people, mostly urologist, who dragged their partners along for one last lecture before the evening reception began. The first sign that something was amiss appeared even before the lecture began. The audience watched as the 57-year-old Brinley climbed the stairs to the lectern, dressed in a blue track suit. Not at all professional attire for this kind of meeting. It's not nervous. Ecology, after all.

I'm very nervous right now. Mm-hmm, you should be. And this track suit stood in sharp contrast to those in the seats who were in their evening best. If the lecture had followed a normal course, perhaps no one would remember the blue track suit. But from the very first slide, it was apparent that this was anything other than a normal talk. I God.

Because the very first slide was a purest slide. was a penis. Yeah. Okay, it's a urology meeting. Penis picks are to be expected. That's not abnormal, right? But this wasn't just any penis. This was Brindley's penis.

Brindley's penis. I knew it. And not just one slide, but dozens. Yeah, lots of his own pain. Well, Brindley explained to his stunned audience, he had no other choice. His hypothesis was that

if you injected vasoactive agents like papavarian and fentolamine into the penis, you could induce an erection. But lacking easy access to an appropriate animal model, he decided to test it out on himself. Uh-huh. It doesn't end here, unfortunately. Because while a picture may be worth a thousand words, a live demonstration, you can't put a price on that. No, you really can't. That's why you need a track suit. Mm-hmm.

Brindley was worried that the audience wouldn't believe that the erection featured in these pictures. was induced by the injection alone. And so prior to the lecture, he had injected himself with papyvierin and deliberately wore his loose track suit so that he could pull his pants tight against himself, which is exactly what he did after stepping out from behind the podium. As to what happened next, let me read you this quote from one of the audience members. Quote, at this point, I and I believe everyone else in the room was a gog. I could scarcely believe what was occurring on stage, but Professor Brindley was not

satisfied. He looked down skeptically at his pants and shook his head with dismay. Unfortunately, this doesn't display the results clearly enough. He then summarily dropped his trousers and shorts, revealing a long, thin, clearly erect penis. There was not a sound in the room. Everyone had stopped breathing. The sense of drama in the room was palpable. He then said, with gravity, I'd like to give some of the audience the opportunity to confirm the degree of tumessence. With his pants at his knees, he waddled down the stairs, approaching to their horror, the urologists and their partners in the front row. As he approached them, four or five of the women in the front rows threw their hands up in the air and screamed loudly. The screams seemed to

shock Professor Brindley, who rapidly pulled up his trousers, returned to the podium, and terminated the lecture. End quote. He didn't realize that maybe this was inappropriate until people screamed. I mean, okay, so I have so many thoughts on this. So many thoughts on this. I was processing this story for days. It's so many, it's so many, you're at a conference, a meeting, and you, I mean, I don't have the right words. This is a guy who doesn't have friends to tell him, hey, man, maybe not. You can't drop trow on stage at a scientific conference. I mean, and let's be real, you shouldn't need to have friends who are your moral guideposts like that. Like, that should be something that you know to not do.

Right. You can't do that. You cannot, you cannot do that. But he did. Okay. He did. And so what can we take away from Brindley's lecture? One, and this is the thing that's most often referenced when, you know, this is mentioned in any article or book about Viagra, is that his demonstration showed that you could induce erections with a vasoactive compound. And this was 15 years before Viagra came on the market. And so this is why this story is often mentioned because it's like, oh, this is proof that people had been working on medications for erectile dysfunction long before Pfizer got into the game. And sort of the same physiological basis was used as like how to induce an erection. Yep. Okay, fine. That's the first thing. But the second thing that we can take away.

And this is the thing that I didn't see mention in any articles. or books that included the story is, excuse me, but like, what? What? Yeah. What? Like, how was this allowed to happen? How was this not disciplined afterward? And how has no one commented on how messed up this was?

Yeah. Like, not only that, but people generally write about Brindley as this quirky, eccentric guy whose lecture was unique, dramatic, paradigm shifting, and unexpected. This is a quote. right, from the unique. It is difficult to imagine that a similar scenario could ever take place again, end quote. I mean, I certainly hope not. No kidding. I mean, it's the same thing we see time after time with certain people getting away with anything if their work is seen as valuable. Right, like literally exposing your erect penis to an entire room without consent. Yes. Or even warning. Like, I mean, not even warning much less consent.

Not like, hey, what you're about to see is, you know, pictures of a penis on whatever. Like that's, we can even, okay. I would honestly expect it at a urologic society conference, though I would still expect in the 80s some kind of warning. Like, I don't know. In the 80s? I don't know. I guess you're right. Today, I guess.

That's generous of you. Yeah. Sorry. Yeah. But it's just, it's amazing. Like the article where I pulled these quotes from is titled How Not to Communicate New Scientific Information. And it was written in 2005. And it's still, Brinley is like, what a quirky guy.

This was so unforgettable. Wow. He goes down in history as a really eccentric dude. So wait, sorry. This is an article about how not to communicate things. Are they lifting him up as an example of good job? No. It's mostly like cheeky.

Like, wow, what a guy. I can't believe he did this. What a scoundrel. So, I mean, the reflection still not there. I mean, 2005 was 20 years ago. But still. Yeah. All right. Okay. So I've already given enough airtime to Brinley. Let's get back to Viagra. The 1970s and 1980s saw a number of developments that set the stage for Viagra's introduction. Injections with phoactive compounds that gave people erections, erectile dysfunction perceived as a deviation from the norm. rather than a normal part of aging, and the switch in thinking of erectile dysfunction's cause

from psychogenic to organic. All of these things opened the door to reframing ED as a medical condition that affected quality of life, and thus was a therapeutic target. It's true that Pfizer didn't set out to make an erectile dysfunction drug, but this reframing made it possible for them to seize the opportunity when it presented itself, which it did. in 1992. Pfizer had, for a few years, been working on a medication to treat angina, experimenting with a few different compounds, including one called sildenafil citrate, which had been synthesized by Pfizer in their sandwich labs in the UK. Essentially, they were looking for an alternative to nitrates, which worked in the short term but became less effective over time

as tolerance developed. Early studies showed that sildenophil dilated the blood vessels, lowering blood pressure, a good thing because it meant sending more blood to the heart, but it could also lower blood pressure too much when used in combo with nitrates, as you mentioned, Aaron, and that was a common prescription for their intended consumer group. Plus, the short half-life of syl xenophil meant you had to take it three times a day, which was not ideal, and it was associated with a few adverse events, like indigestion, headache, and erections. specifically more frequent and longer-lasting erections.

And that's how it was described, like erections were labeled or were described as an adverse event. Despite what later versions of the story would have you believe, there was no light bulb moment where Pfizer scientists proclaimed, finally, an erection drug. Initially, this side effect was just kind of noted down along with the rest of them. And even if someone did spend a few minutes of thought on it, sildenafil didn't seem like it would be the best ED drug. The increased erection didn't happen until a few days after taking the drug, which you had to do three times a day. And the clinical trial involved young men.

So there was no reason to think that it would have the same effect in older men who had ED, along with vascular disease. Okay. So if you wanted an erection on Saturday, you'd have to start taking the meds on Wednesday and not skip one of your three daily doses. Interesting. Yeah. Based on their studies as an adverse effect.

Right, right. Because this was not like at this point, sildenophil had not been tested specifically for directions. Right, right, right, right. But even with all these odds stacked against sildenophil, researchers still thought it might be worth a shot. They had the molecular action of sildenophil mostly figured out. So they reasoned that maybe soldenophil,

in the absence of sexual stimulation equals no erection, but syldenafil plus sexual stimulation equals erection. And so Pfizer put together a couple of pilot studies in 1993 and 1994, testing sildenafil for the treatment of ED. They recruited volunteers with ED, gave them sildenafil or placebo, put them in a private room with erotic materials, and then monitored their erections using a device called the ridgy scan. Yes, that's the actual name. Ridgy scan. Love it. A note on the rigid scan. 60% rigidity was considered successful. Okay. Which corresponded to the amount of rigidity for vaginal

penetration. So quite a heteronormative measurement there. Not surprising. It's not surprising. Everything about erectile dysfunction is very heteronormative. Interesting. Yeah. The results of of these pilot studies were promising. Sildenafil seemed to work, and what was even better was that it worked after a single dose. This opened the door to larger clinical trials involving thousands of individuals, which were also successful. Participants allegedly didn't want the trial to end, so Pfizer got permission to keep them enrolled in a long-term trial. This is from someone affiliated with Pfizer, so, you know, grain of salt. In fact, actually a lot of the papers, a lot of the papers, both about the history, but especially about the effects of Viagra or Sildenafil are, like,

you can look and you're like, oh, Pfizer Labs. Yeah. Oh, Pfizer. That's not surprising. That's not surprising. Yeah. There did seem to be a few worrying side effects, which you touched on a little bit, Aaron. But by and large, it seemed relatively smooth sailing for Pfizer and Saldanphil, in large part

because its safety had already been assessed in previous years. So in 1997, Pfizer filed a new drug application for Viagra, as it was now known, with the FDA. The FDA gave Pfizer priority review status, which is used for drugs that, quote, represent major advances in treatment or fulfill a significant medical need. Wow. Okay. Within a year, the FDA approved Viagra for treatment of erectile dysfunction, and the first oral medication for ED landed on the market in 1998. Viagra's launch was anything but a quiet slipping onto the market, and it drastically changed

the marketing landscape for pharmaceuticals. You might think that an erectile dysfunction drug kind of sells itself, but in fact, at the time, similar medications or devices were considered kind of seedy, and so Pfizer had to carefully strategize their marketing campaigns. One way they did this was to make it clear that Viagra was for only certain kinds of people. Essentially, the straight, married, middle-class, older white men that they featured in their early ads, many of which didn't necessarily say or focus on erectile dysfunction or Viagra outright. Or if they did, they made it very clear that erectile dysfunction was entirely a medical issue, not a psychogenic one. These ads also portrayed Viagra as a relationship drug, promising to restore happiness as well as masculinity.

as narrowly defined in these ads. Pfizer was also one of the first to use celebrity spokespeople, like Bob Dole, in advertisements, and paid consultants like urologists to appear on daytime talk shows or in commercials. And importantly, these consultants didn't readily reveal their connection to the company, instead portraying themselves as unbiased experts. Whoa. Shade. This direct-to-consumer advertising seems super familiar to us now, although still bizarre and icky and dystopian.

Like, I don't have regular TV. And so when I'm like in a hotel and they're commercial after commercial after commercial for drugs. Every single commercial is for a drug and it really drives me crazy. It's horrible. Especially because very much like the ad for Viagra where they didn't even say Viagra. Like now they all say the drug. But a lot of times they won't say the condition even. So it'll make everyone who's listening think, well, I need to go talk to my doctor about this medicine. I have no idea what it's for, no idea what it's treating.

But everyone on the TV needs it and they're so happy. Right, right. Look at me. I can eat yogurt happily again. Right. Look at me. I'm playing in the sunshine, flying a kite. What?

Pushing my grandchildren on a swing. Like it's just, yes. Yes. We laugh, so we don't cry. But yeah, at the time that Viagra was released, this sort of direct-to-consumer marketing was super new. The FDA had only lifted the ban on these types of ads six months before the drug was released. Also, they used to be banned and then they were lifted. I'm so curious.

We need to do a whole episode on that. Yeah, we really, we really, really need to. The World Wide Web, which was relatively new in 1998, also provided another avenue for people to gain more information about Viagra and to try to buy the drug online without a prescription. Viagra was the butt of a million and one late-night talk show jokes. It made appearances in storylines on TV shows, and soon everyone knew the name of this drug.

Yeah. Many men took the slogan, ask your doctor to heart. And there were some reports that visits to doctor's offices actually increased for some groups of men who made their first appointment in years to ask about Viagra. Erectile dysfunction went from a disorder treated in the 1960s by psychiatrist to then be treated by specialists like urologists to one treated by general practitioners. Within the first three months of its release, Viagra made $411 million in sales. Is that in 1990s?

I believe so, yeah. Holy guacamole! And 2.7 million prescriptions were written in the first three months. Wow. It became the fast. It became the fastest selling drug in history, grossing over $1 billion in its first year, and netting $7.4 billion in total sales for Pfizer in its first five years. I am aghast.

I know. A gog. Just like the audience in Brinley's lecture. Some commentators sung the praises of Viagra, like Bob Guccioni, which I don't know if I'm saying that right, the publisher of Penthouse, who wrote that, quote, feminism has emasculated the American male, and that emasculation has led to physical problems. This pill will take the pressure off men.

It will lead to new relationships and undercut the feminist agenda. End quote. I'm going to lose it. I'm going to lose it. Uh-huh. Less sexist and more reasonable people pointed out that, Viagra had made sex, especially for older adults, more of an open topic of conversation, and it reduced the stigma attached to erectile dysfunction.

But there were some, many, even critics of the drug, mostly centered around fears of how Viagra would change relationships, lead to addiction or recreational use. From an article in time before Viagra's release. Quote, doctors are concerned that an anti-imitance pill could be subject to widespread abuse, Use. Reports indicate that some Hollywood bedroom athletes have already tapped into an underground market for an injectable erection drug. The danger is that otherwise healthy men will take syldenafil to bolster their sexual performance and then become psychologically addicted, unable to achieve an orgasm without it. End quote. Bedroom athletes, Hollywood bedroom athletes.

Love that. What? prior to Viagra's release, Pfizer anticipated this opposition and, quote, sent a delegation to the Vatican to find out how the Roman Catholic Church would respond to the pill. The Vatican gave its blessing on the basis of Viagra's contribution to improving family relations, end quote, and barf. I can't. The Pope approved Viagra? The Pope's seal of approval stamped on every blue pill. Oh my God.

I have so many feelings I can't express them. I mean, not enough time in the world for me to process all of the thoughts and feelings I have. The Pope approved Viagra. Improving family relations. Yeah, family relations. That's what Viagra improves. Absolutely, Aaron. Others drew attention to the manner in which Pfizer had branded erectile dysfunction, accusing them of creating a disease or problem and then inventing and marketing a solution.

Classic capitalism. Then there was the question of normal. Even before Viagra, medicine had sought to create a baseline for what was considered normal and what wasn't in terms of erections, arousal, masculinity, femininity, aging, sexuality, relationships, and bodies in general. By constructing boundaries around what is quote-unquote normal or acceptable, medicine can other people and make them feel like there is something wrong with them, and they should be striving to achieve that normal. We've talked about this before in our menopause episode, sort of the medicalization of a normal part of aging and some of the issues that come with

that. But like we also said in our menopause episode, that doesn't mean that we should completely reject these drugs that might make some people's lives a little easier, a little better or a lot better. Just because something is a normal part of the aging process doesn't mean that we can't or shouldn't do something about it if we want to and if it doesn't harm us. Right. If it's causing problems in your life, like seem like we talked about with menopause. Like, is that totally a normal part? Yes. Is some of it very uncomfortable and impacts your quality of life? Yes. Do something about it. Same thing with ED. Absolutely. Yeah. And so I want to push back a bit on this idea that erectile dysfunction is solely a problem invented to sell a solution. Yeah.

Because clearly millions of people around the world have benefited from the use of Viagra and related drugs and have reported that their quality of life has improved because of them. And the last criticism that I want to discuss is not about Viagra itself, but about what Viagra highlighted when it came to gender bias in medicine and what is considered medical necessity. Ah. Yep. Within a few months of Viagra's release in 1998, most major American health insurance carriers covered it. Also, wow. Yeah. Well, because there were a few lawsuits pending, and so they quickly were just like, all right, we see this coming in our future. Let's just cover it. Within a few months. Do you know how many insurance companies still won't cover OZMPIC and other similar?

I mean, Wagovi more, like not OZMPIC, but the ones that are marketed just for weight loss, that's a whole other thing. It's a whole other thing. Yeah. Wow. Okay. All right. Cool, cool, cool. But this was not the case for birth control pills. Right. When Viagra came out, most people still had to pay for it out of pocket. The year Viagra was released, 1998, women paid 68% more in out-of-pocket health expenses compared to men, because most reproductive health services were not covered. Well, Aaron, birth control is not approved by the Pope.

Right? It's absolutely not. It's very much not. The reasoning was that Viagra is a medical drug intended to treat a legitimate medical condition, while birth control was and is seen as a quote-unquote lifestyle drug. Oh, my God. And therefore, optional. I'm in a vomit.

Never mind the fact that many people use birth control to treat medical conditions, never mind the fact that birth control was approved by the FDA in the first place to treat menstrual. disorders. Viagra also brought to light other differences. For 15 years after its initial release, the birth control pill could only be prescribed to married women who often had to obtain their husband's permission. Only in 1972 were unmarried women allowed to obtain the pill. Can you imagine any law prohibiting an unmarried man from getting Viagra or requiring that he get his wife's permission. Right, so that she knows what he's up to.

Mm-hmm. And I acknowledge that it's a bit apples and orange comparison here. Is it, though? But swap out Viagra with male birth control, and the point remains. And finally, there's the sheer existence of Viagra, which was made possible only by years of studying the decline in erections over a man's life. Similar studies in women happening at the same time were few. and far between, tinged with sexist assumptions, and kind of came to the conclusion, well,

who even knows? There's just too much going on here. Women are just too complicated. The switch from impotence is a psychogenic disorder to erectile dysfunction is an organic condition, happened lightning fast. Compare that to the long, long tradition of women being told that it's all in their head. Even when it comes to, quote-unquote, female Viagra, it's the same thing. Quote, is it a mind or body problem? End quote, read the cover of a 2000 copy of Newsweek. In early studies of vasoactive drugs for female sexual dysfunction, participants were required to see a sex therapist first, who, quote, evaluates the context in which the patient experiences her sexuality, her self-esteem, and body image, and her ability to communicate

her sexual needs to her partner." Oh, it's hormonal. Oh, it's about blood flow. Oh, it's all in her head. Oh, it's about her partner. Oh, it's about the general state of the world. Oh, maybe it's a combination of all of them and we'll never figure it out. How about arousal is not the same for everyone?

But part of the issue seems to stem from the fact that the study of female sexual dysfunction takes the blueprint from male erectile dysfunction. Researchers are looking for a direct parallel. What is the female equivalent of an erection? But what if there isn't one? In these studies, what is the outcome that the researchers are looking for? And how are they measuring it? Is it vaginal lubrication?

Is it clitoral engorgement? Is it perceived arousal? Is it orgasm? Or is it some mix? Why has it taken? taken so long to develop a female Viagra? Great question. Let's tell that story someday. Also, Erin, it hasn't changed. I mean, first line on up-to-date for female sexual arousal disorder is CSX therapist. Right. And it's never considered like, oh, erectile dysfunction is so simple

because we've been studying it for so much longer and we've put so much more funding into answering this question, but female arousal, female sexual dysfunction is so complicated because we don't really care about it and we haven't cared about it. It's such a mystery. It's also like, it does a disservice to everyone because like, A, sex therapy is great. That's exactly what I have here. Yeah, because what Viagra did is that it reduced male arousal to one dimension. Right. And it led many researchers to do the same for female arousal. This is not good for anyone, right? And I think that this is a really undertold part of the story where it's like Viagra is great.

And if it works for you, whether you're, whether the ultimate cause of erectile dysfunction is psychogenic and Viagra is working because it's whatever, helping you overcome that. It makes things easier than you're less in your own head, whatever it is. Right, whatever it is. But it's like, shouldn't we consider the whole picture instead of being like, it's blood flow. Right. It's blood flow. It's blood flow.

And for women, we don't really know. We don't seem to be just blood flow for you. So, sorry. Best of luck. Yeah. I think this is why the story of Viagra is so fascinating to me is because of all of these dimensions, is because of the huge legacy that it has had on marketing, on sexuality, on the way that we talk about drugs and on like blockbuster drugs.

I mean, everything. Yeah. And so I'm really curious, Erin, what you can tell me about Viagra. today? I don't know. Not much. I think we've covered it all, but I'll try and wrap us up right after this break. Erin, we already talked about a lot of the statistics when it comes to the prevalence of erectile dysfunction, which again nears 100% in those over age 70, 50 or more percent as you, like it increases, it's estimated to increase with each decade, usually over age 40. So starting from like 40, 50, around age 40 and kind of going up from there.

Exactly how are these statistics determined? It's a little bit unclear from all of the papers that I read. And that is not to, like we've mentioned, undercut the importance of erectile dysfunction in a person's sexual health, because we already underappreciate sexual health, especially in U.S. healthcare. Like it is just ignored across the board for a lot of people. and Viagra and similar medications are often seen as this kind of easy fix, a blanket fix for any kind of erectile dysfunction.

When is that the fix for everyone? Maybe, maybe not. There's also statistics that I saw in a number of papers that I don't know where these came from and they weren't good, but also that estimate that a large proportion of people who maybe have erectile dysfunction or are suffering in some way with their sexual function, don't actually ever access even a drug as ubiquitous as Viagra. So there's, again, just a lot of it comes down to the way that we communicate about sexual health and the taboos that are still in existence about sexual health, even though Viagra has become sort of the butt of so many jokes and is so easy to come by these days. Right. It's also estimated that in the U.S., the cost of treatment, for erectile dysfunction is $15 billion a year.

How much do we spend on female sexual health? Almost nothing, probably, in comparison. I have a question. Did you come across any studies looking at the effects of Viagra on women? Great question. I didn't. I know that they do exist. I probably should have spent more time looking for them specifically, but I know that

they do exist. And I know that there are other, there are other medicines that are targeting, like, sexual dysfunction specifically. The one that I know of the most is not like a vasodilator. It doesn't work in that way. It's more closely related to like the SSRIs. It like works, I think, in relation to serotonin, which is another neurotransmitter that is very much involved in like the erectile process as well. But yeah, it is a area much less explored. Okay. But but but in terms of like women taking Viagra specifically. Women taking Viagra.

It is a thing that has been done. I don't know the stats on it. Oh, okay. Yeah. Yeah, I don't know the stats on it. There are, though, also a lot of other treatments for erectile dysfunction aside from Viagra. There's similar medicines like the Cialis or to Dallophil and others, some of which are now approved to take on a low dose daily basis rather than an as-needed basis, which is how

Viagra has always been taken and marketed. There are also other things like vacuum devices, which use negative pressure to stimulate blood flow that helps the process along. There's injectable medications. There's suppository medications. There's other surgical interventions, especially depending on the cause of the erectile dysfunction to begin with. And you might need a surgical intervention. Some of these are like semi-rigid all the time. Some of these have pumps that you physically pump up when you need. But there aren't, as far as I could tell, at least as of 2019,

any new oral medicines that are targeting very novel biochemical pathways to treat erectile dysfunction. There's also a lot of supplements and nutraceuticals that are at your own risk, entirely unregulated, see our supplements episode. And then there's newer therapies, like shockwave therapy or PRP, all of these very, I don't know, there, I have a couple of papers,

if you want to go in detail on what the evidence of these are. They're all still very much in trials and not anything that's available on the market. But there is still a hefty amount of research going on on new and better ways to treat erectile dysfunction. It's a profitable business. It really, really is. One thing that I want to add, just, I know that someday we will do a female Viagra episode because I think that is really needed. But I think that like if we demand equal funding to find a female Viagra, we should also demand equal evidence that what we find is therapeutic and not full of side effects and is as easy to take as Viagra. that it actually does what it claims to rather than just paying lip service to equality in medicine.

Capitalism masquerading is feminism, which is I think some of the problems that are associated with some of these female Viagoras today where it's just like, look, we did it. Right. This is what you've been asking for. It's the equivalent, oh, don't mind those side effects. Oh, don't mind this.

Don't mind that the evidence is kind of, you know, a little bit vague and leave something to be desired. Well, and to do that, we would need to do a lot more research on sexual health in general. Yes. Yep. But yeah. Sources.

Sources. I have a bunch. I didn't really, like, I honestly, I feel like a lot of these were grain of salt. And again, like I mentioned in terms of where they came from, which was people who were working with Pfizer at the time, or were kind of one-dimensional in other aspects. Anyway, there was a book called The Rise of Viab. How the Little Blue Pill changed Sex in America. And this is from like shortly after, just a few years after its release by Micah Lowe.

And then if you want to read more about like the detailed how Pfizer found this or how Pfizer like decided to shift their focus to sildenophil as a treatment for a rectal dysfunction, there's a book titled simply Sildenafil. And there's a chapter about the discovery of Sildenafil. Love it. Yeah. A whole book. phenomenal. I have a lot of papers that go far more into the detail of the neurobiology and like biochemical pathways of erections. There was a paper that I found really helpful by Dean and Lou from 2005 called Physiology of Penile Erection and Pathophysiology of Arrectile Dysfunction.

Another by Grotsky et al from 2010, anatomy physiology and pathophysiology. physiology of erectile dysfunction, a few others that are specific to sildenophil and like the pharmacology more of sildenophil and other medications, and at least one on other ways that we use it. Because again, we use this medicine for other things too. But you can find the list of our sources, all of them from this episode and every one of our episodes on our website, this podcast will kill you.com, and it's under the episodes tab. That's where it is. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Leanna Scolachi and Tom Brifogle for the audio mixing.

Thank you to everyone at exactly right. And thank you to you, listeners. Hopefully you found this episode enjoyable, learned something new. Yeah. As always, reach out, let us know what you think. Have an image seared in your brain that we'll never go away. Friendly, man, yeah. And a special thank you to our wonderful patrons.

We really do appreciate your support. Like, it means so much to us. It really does. Thank you. Until next time, wash your hands. You filthy animals. Running my small business was like playing basketball five on one, and I was the one.

Now, QuickBooks gives me access to a team of AI agents and trusted experts for the assists I need. Nothing but, Nick. Outdo it with Intuit QuickBooks. Feature availability varies by product. Success starts with your drive, and American Public University is here to fuel it. With affordable tuition

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