How Viagra Works

For many people, talking about the penis is tough. This area of the body is considered private and isn't discussed publicly (well, not in polite company). However, the penis is simply a part of the male anatomy designed to accomplish a task, and we'll treat it that way here.

In the case of the penis, there are actually two tasks that it handles:

Viagra helps with the second task: ejaculation.

When things are working properly, ejaculation is a three-step process:

That sounds simple enough, but in many cases, step two doesn't happen, making step three difficult or impossible. Although the man is stimulated, the penis doesn't become erect. To understand why, you need to understand the technology of an erection.

When you want to move nearly any part of your body, you do it using muscles. Whether you're moving your fingers, toes, arms or legs, muscles do the work. Even when you stick your tongue out, you do it using muscles:

Muscles let you move your body voluntarily with precise control.

The penis, on the other hand, is completely different. There are no muscle contractions involved in making the penis erect. To become erect, the penis instead uses pressure.

Probably the easiest way to understand how the penis becomes erect is to think about a balloon. If a balloon has no air in it, it's limp. As you inflate a limp balloon with just a little air, it becomes elongated and rigid.

The penis uses a similar mechanism, but instead of using pressurized air to become rigid, the penis uses pressurized blood. The penis contains two cigar-shaped structures, called corpora cavernosa (singular: corpus cavernosum), that it uses to become erect.

Think of the corpora cavernosa as balloonlike tubes. Arteries­ bring blood into these two tubes, and veins carry blood away from them. The penis can be either limp or erect, depending on the flow of blood:

If the arteries leading to the penis don't open up properly, it's difficult or impossible for a man's penis to become erect. This problem is the leading cause of erectile dysfunction (ED).

To solve an erection problem when the cause is poor blood flow, you need to open the arteries. Let's take a look at how this can be done -- and how it was done before Viagra.

The first real breakthrough in the treatment of erectile dysfunction came in 1983. Prior to that time, it was thought that erectile dysfunction -- the inability to achieve an erection -- was primarily mental.

That concept came crashing down at the 1983 American Urological Association meeting in Las Vegas when Dr. Giles Brindley injected his penis with the drug phentolamine. Following the injection, Brindley appeared on stage and dropped his pants to display one of the first drug-induced erections to the incredulous audience of urologists.

What did the phentolamine do? It relaxed a muscle.

Inside the body there are several kinds of muscle:

Smooth muscle plays a key role in every erection, and phentolamine is a drug that relaxes smooth muscle.

The reason why an injection of phentolamine produced an erection was especially interesting in 1983 because no one had really thought about it before. Here's what happened:

Starting in the mid-1980s, it became common for men with erectile dysfunction to inject smooth-muscle-relaxing drugs as a treatment for the problem.

Viagra makes the process a whole lot easier by doing the same kind of thing with a pill instead of an injection. Another advantage of Viagra over an injection of phentolamine is that Viagra only causes an erection when the man is sexually aroused. Phentolamine, by contrast, causes an immediate and uncontrolled erection.

How can a pill work only on the smooth muscle in the penis and not the entire body, and only when the man is aroused? The answers to these questions begin with an understanding of how blood flow works in the body, so let's start there.

To understand how to make a penis-specific drug, think about the way blood flows in your body. Your body has just one pump -- the heart. But different parts of the body need different amounts of blood at different times. For example, if you're running a marathon, your body needs to send more blood to your arm and leg muscles, and it may want to cut most of the blood flowing to the stomach (and other nonessential organs) in order to save oxygen for the legs.

What your body needs, in other words, is a set of valves that it can use to increase and decrease blood flow to certain parts of the body -- and your brain needs a way to control them.

The mechanism that the body uses to open a valve in any part of the body is a simple little chemical machine:

There is one final part to this chemical machine: Another enzyme, called phosphodiesterase (PDE), is deactivating the cGMP all the while.

­cGMP is produced as long as the brain is sending messages down the nerve fibers in the artery. When the brain stops sending the signal, all of the cGMP goes away because PDE is deactivating it. This is how the brain turns valves on and off whenever it wants to.

Later, we'll learn how Viagra works its magic, discuss some of the side effects and even new competitors on the market. But first, let's delve deeper into the chemistry.

When couples talk about having "chemistry" together, who knew it was such an accurate description?

The brain sends signals to NANC cells in the artery. The NANC cells release nitric oxide (NO). Nitric oxide acts as a signaling molecule and stimulates an enzyme called guanylate cyclase in nearby cells. The guanylate cyclase converts a chemical called GTP into another chemical called cGMP. cGMP causes muscles in the walls of the arteries to relax. This relaxation increases blood flow. Meanwhile, PDE is decomposing the cGMP and turning it back into GTP. There is a cycle -- guanylate cyclase turns GTP into cGMP, and PDE turns cGMP into GTP. Nitric oxide turns the cycle on.

­cGMP is produced as long as the brain is sending messages down the nerve fibers in the artery, which generate nitric oxide and keep the cycle going. When the brain stops sending the signal, all of the cGMP goes away because PDE is deactivating it. This way, the brain can turn valves on and off whenever it wants to.

So how does this relate to an erection?

When the brain gets aroused, it sends a signal to the penis. Nerve cells in the penis' corpora cavernosa start producing nitric oxide, which leads to the creation of cGMP. The cGMP causes arteries in the corpora cavernosa to dilate, causing lots of blood to flow into the penis. The extra blood flowing in causes the penis to inflate like a balloon. An erection occurs.

When a man has erectile dysfunction, there can be many reasons for the problem. But one of the most common reasons, especially in older men, is that the arteries in the penis aren't dilating enough when the brain sends the signal. The man is aroused and the nerves in the penis are producing nitric oxide, but the amount of cGMP produced isn't enough to maintain an erection.

The way that Viagra goes about solving this problem is quite ingenious.

If you want to create a drug that increases blood flow to the penis, there are at least three ways to do it:

Viagra uses method No. 3 -- it eliminates the PDE that is decomposing the cGMP, so cGMP builds up in the penis and has a larger effect on the artery walls. The greater the amount of cGMP, the greater the blood flow, and the greater the blood flow, the greater the degree of the erection.

The reason that Viagra uses this technique is because of an interesting quirk of PDE. It turns out that the human body has at least 11 different kinds of PDE that it produces. Only one of them -- PDE5 -- is found primarily in the penis. Once scientists discovered this fact, the creation of Viagra was relatively simple. All that Pfizer needed to find was a chemical that would selectively block PDE5 and nothing else. With the PDE5 blocked, cGMP could build up in the penis and increase the blood flow there without affecting other parts of the body.

Earlier, we talked about the enzyme PDE. To better understand its function, consider that an enzyme is a specially folded protein that can speed up a chemical reaction. (For example, the article How Cells Work describes the maltase enzyme.)

In the accompanying diagram, you see that maltose is made of two glucose molecules bonded together (1). The maltase enzyme is a protein perfectly shaped to accept a maltose molecule and break the bond (2). The two glucose molecules are then released (3). A single maltase enzyme can break more than 1,000 maltose bonds per second, and will only accept maltose molecules.

PDE5 is an enzyme that accepts cGMP and breaks it down. Pfizer needed a chemical that would gum up PDE5 and keep it from doing its job. The chemical that Pfizer discovered is called sildenafil citrate. It fits right into the PDE5 enzyme and disables it.

Viagra contains sildenafil citrate packaged as a pill. When a man takes a Viagra pill, the sildenafil citrate flows throughout his body, but it really only affects the PDE5 enzyme in the penis. The drug stays in the bloodstream for about four hours, and then it's washed out of the blood by the liver and kidneys.

And that's the end of the "how it works" part of the Viagra story:

This works perfectly for the majority of men -- except for a few minor problems.

Very few drugs work perfectly, and Viagra is no exception.

­The first problem comes because Viagra happens to have a spillover effect. It blocks PDE5, but it also has an effect on PDE6. It turns out that PDE6 is used in the cone cells in the retina, so Viagra can have an effect on color vision.­ Many people who take Viagra notice a change in the way they perceive green and blue colors, or they see the world with a bluish tinge for several hours. For this reason, pilots can't take Viagra within six hours of a flight.

The second concern comes for people who are taking drugs like nitroglycerin for angina. Nitroglycerin works by increasing nitric oxide, and it helps with angina by opening up the arteries that supply the heart with oxygen. If you take nitroglycerin and Viagra together, the increased nitric oxide plus the blocking of PDE5 can lead to problems.

Other issues with Viagra can include little things like headaches (the drug, as a side effect in some men, opens up arteries in the brain's lining and causes excess pressure) and big things like heart attacks. The possibility of heart attacks is one reason why Viagra is a prescription drug rather than an over-the-counter drug like aspirin. A doctor needs to understand your medical history and make sure that Viagra won't cause a heart attack.

Viagra's most famous possible side effect? A long-lasting (as in, several hours long) and painful erection.

Finally, there's concern that some men -- especially younger men who take Viagra recreationally and who don't really need it for physical reasons -- may end up with a dependency on the drug and become unable to maintain an erection without taking Viagra.

Viagra is a hugely successful drug, so other drug companies of course want a piece of the action. They developed different chemicals to block the PDE5 enzyme and created two new drugs: Cialis (tadalafil) and Levitra (vardenafil). (There is another drug, Staxyn, with the same active ingredient as Levitra that has recently come onto the market. It's an orally disintegrating tablet that isn't interchangeable with Levitra, but chemically is much the same.)

Because Cialis and Levitra block the PDE5 enzyme, they work exactly the same way as Viagra. They help men who have trouble maintaining an erection because of blood flow problems, and they only work when the man is sexually aroused.

Because they block PDE5 with different chemicals, however, there are some differences between the three drugs. For example:

There are always new drugs in development. Here are a few future possibilities:

Want to learn more about erectile dysfunction and sexual conditions? There are lots more links on the next page.