MAY/JUNE 2004

AROUND HARVARD

This article originally appeared in the April 2004 Harvard Men's Health Watch and is provided courtesy of Harvard Health Publications.

Pills for erectile dysfunction: Viagra, Cialis, and Levitra

Nothing succeeds like success. In our fast-paced world, new products that work well gain acceptance so quickly that they are soon taken for granted. That’s just what happened with the treatment for erectile dysfunction. Many of us can hardly remember the bad old days, when there was no effective oral treatment for the problem that plagues 30 million American men. But that’s the way it was until 1998, when Viagra burst onto the scene.

Imitation is the highest form of flattery, and it doesn’t take long for a successful innovation to attract competition. And so, a scant five years after Viagra revolutionized male sexuality, it was one of three pills for erectile dysfunction. Call them Viagra, Levitra, and Cialis (or check out their high-octane ads), and they sound like entirely different medications. But call them sildenafil, vardenafil, and tadalafil, and they sound like closely related chemicals. In fact, they have many more similarities than differences. But with three companies fighting over Viagra’s $1.7 billion market, the media drumbeat is well under way.

Men who need help with their erections should not be drawn into a popularity contest between company spokesmen like Senator Bob Dole, coach Mike Ditka, and baseball star Rafael Palmeiro. Instead, they should understand the many similarities and subtle distinctions that characterize these rival medications.

How they work
The three drugs are so similar because they share a common target, an enzyme called phosphodiesterase-5 (PDE-5). To understand why blocking PDE-5 improves sexual function, you have to know how erections develop.

Normal erections require a receptive state of mind, adequate levels of testosterone, and healthy arteries, veins, and nerves. But they also require a tiny chemical messenger called nitric oxide (NO) that serves two crucial functions: transmitting the impulses of arousal between nerves and relaxing the smooth muscle cells in the arteries, allowing them to widen and admit more blood to the penis.

Nitric oxide is essential for a normal erection because it signals the arterial cells to produce cyclic guanosine monophosphate (cGMP), the chemical that actually increases the flow of blood to the penis. But the tissues of the penis also produce PDE-5, the enzyme that breaks down cGMP.

In normal circumstances, the penis generates enough cGMP to produce a rigid erection and enough PDE-5 to end the erection when ejaculation is complete. But in many men with erectile dysfunction, this intricate system is out of balance. Often, these three medications can make it right. By inhibiting PDE-5, they increase the supply of cGMP and, in many men, the extra cGMP will allow erections to develop in response to sexual stimulation.

How well do they work?
In test tubes, vardenafil (Levitra) and tadalafil (Cialis) inhibit PDE-5 somewhat more effectively than sildenafil (Viagra) does. But laboratory potency doesn’t necessarily predict clinical activity. In this case, it means that lower doses of the newer drugs will achieve results that are comparable to the older drug’s success rates. Vardenafil is marketed in 2.5-, 5-, 10-, and 20-mg tablets; tadalafil in doses of 5, 10, and 20 mg; and sildenafil in 25, 50, and 100 mg. Each produces better results at higher doses, but the top doses are also more likely to cause side effects. And all the drugs are more effective in men with mild erectile dysfunction than in those who are severely impaired.

Doctors have had much more clinical experience with sildenafil than its newer rivals. Still, all three drugs appear to achieve similar results. In broad terms, about 70% of men benefit. The response is best in men with no identifiable organic cause of erectile dysfunction (about 90%), but it’s less favorable in diabetics (about 50%), and it’s hard to predict in men who have been treated for prostate cancer.

How safe are they?
All three drugs are very safe for healthy men. The most common side effects are headaches and facial flushing, which occur in about 15% of men. Other adverse reactions include nasal congestion, indigestion, and back pain; visual disturbances are less common. In almost every case, the side effects are mild and transient. Prolonged painful erections are more serious, but this complication (priapism) is rare.

Because these drugs all act on arteries, men with cardiovascular disease require special precautions. All arteries generate nitric oxide, and all rely on enzymes in the phosphodiesterase family to regulate the supply of nitric oxide. Drugs that inhibit a phosphodiesterase increase the supply of nitric oxide, thus widening the arteries. Fortunately, these three medications are all highly specific for PDE-5, which is concentrated in the penis. But other arteries contain some PDE-5, and the medications have some action on closely related enzymes elsewhere in the body. That means that any of the drugs can widen arteries and lower blood pressure.

Nitrates are medications that dilate arteries by increasing their supply of nitric oxide. That’s how they widen the partially blocked coronary arteries in patients with angina. But because the nitrates and the anti-impotence drugs all act on nitric oxide, they do not mix. Men who are taking nitrates cannot use sildenafil, vardenafil, or tadalafil. This ban includes all preparations of nitroglycerin (short-acting, under-the-tongue tablets or sprays), long-acting nitrates (isosorbide dinitrate or Isordil, Sorbitrate, and others, and isosorbide mononitrate, Imdur, ISMO, and others), nitroglycerin patches and pastes, and amyl nitrate (so-called poppers, used for sexual stimulation by some men).

The oral medications for erectile dysfunction are quite safe for men with stable cardiovascular disease who do not take nitrates. This group includes patients with stable angina, previous heart attacks, mild congestive heart failure, well-controlled hypertension, and previous strokes. But men with recent heart attacks and strokes should wait until they have recovered fully, and patients with unstable blood pressures, active angina, or other potentially difficult problems should hold off and get specific medical guidance.

Differences
Although the drugs are very similar, they are not identical. The differences depend mainly on how quickly they are absorbed and how long they remain active in the body.

Because dietary fat impairs the absorption of sildenafil, it should be taken on an empty stomach. Vardenafil and tadalafil may be taken with or without food, giving them an advantage — but none of the three should be taken with alcohol. Men who take alpha blockers, such as Hytrin or Cardura for benign prostatic hyperplasia (BPH) or hypertension, should not use vardenafil or tadalafil, but they can take sildenafil (with caution).

Sildenafil exerts its maximal effect between 1 and 4 hours after it is taken, but some men respond within 20–30 minutes, and others retain its benefits for as long as 12 hours. Vardenafil acts faster, sometimes within 16 minutes, and it may last a bit longer than sildenafil. Tadalafil is the tortoise of the group. It takes about 45 minutes to kick in, but it’s also the endurance champion, with activity that persists for up to 36 hours after a dose.

The drug manufacturers have seized on these differences to tout their products’ greater convenience and to boast that they permit more sexual spontaneity. While these claims are grounded in fact, they may not be very important to mature men for whom sexual activity is more likely to involve planning and predictability than urgent impulses and unexpected opportunities. And although a longer duration of action may provide convenience and freedom, it might also produce problems for men who experience side effects. In particular, men with coronary artery disease are better off with a short-acting drug in case they develop an unexpected need for nitroglycerin the day after using a pill for erections.

Decisions, decisions
Which of the three medications is best for you? Until head-to-head trials are performed, it’s impossible to be sure. At present, the greater experience with sildenafil is a plus. For a few men, though, the more rapid action of vardenafil or the longer duration of tadalafil will be a significant advantage. Men who do not develop satisfactory erections with one preparation can ask their doctors about trying another — but men who have had serious side effects from one should stay away from the others.

In the long run, insurance coverage and cost may be the deciding factors. For now, the economic differences are disappointingly minimal, but if the free enterprise system works as it should, a winner will eventually emerge. If that happens, we’ll all be winners.

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